The physiology and pharmacology of mammalian basal ganglia

Progress in Neurohioh)oy. Vol. 14, pp. 221 335.

0301-0082/80/06014)221505.00/0

© Pergamon Press Ltd. 1980. Printed in Great Britain.

THE P H Y S I O L O G Y A N D P H A R M A C O L O G Y BASAL G A N G L I A

OF MAMMALIAN

A. DRAY Department of Physiology, Duke University Medical Center, Durham, North Carolina 27710, and Department of Pharmacology, University of Arizona, Health Science Center, Tucson, Arizona 85724, U.S.A. (Received 5 December 1979)

Contents 1. Introduction 2. The basal ganglia and neurological disease 3. The striatum 3.1. Morphology 3.2. Striatal afferent projections 3.2.1. Cortico-striatal projections 3.2.1.1. Electrophysiology of striatal neurones 3.2.1.2. Electrophysiology and transmitter identity of the cortico-striatal projection 3.2.2. The thalamo--striate projection 3.2.2.1. Electrophysiology of thalamo--striatal projection 3.2.3. The nigro-striatal projection 3.2.3.1. Electrophysiological studies 3.2.3.2. Pharmacological studies 3.2.4. Brainstem-striatal projections 3.2.4.1. Reticular formation 3.2.4.2. Raphe-striatal projection 3.2.4.3. Amygdala-striatal projection 3.2.4.4. Nucleus-accumbens-striatal projection 3.2.4.5. Locus-coeruleus-~striatal projection 3.3. Striatal efferent systems 3.4. Neuropharmacology and microphysiology of transmitters in the striatum 4. The globus pallidus 4.1. Morphology 4.2. Connections of the globus pallidus 4.2.1. Striato-pallidal projection 4.2.1.1. Electrophysiological studies 4.2.2. Subthalamo--pallidal projection 4.2.3. Other pallidai afferents 4.3. Pallidal efferent systems 4.3.1. Pallido-subthalamic projection 4.3.2. Pallido-thalamic projections 4.3.3. Other pallidal projections 4.3.3.1. Pallido-tegmental fibers 4.3.3.2. Pallido-habenular fibers 4.3.3.3. Pallido-nigral fibers 5. The subthalamic nucleus 5.1. Morphology 5.2. Subthalamic efferent projections 5.3. Subthalamic afferent projections 5.3.1. Cortico-subthalamic projection 5.3.2. Raphe-subthalamic projection 5.4. Neurotransmitters in the subthalamic nucleus 6. The substantia nigra 6.1. Morphology 6.2. Efferent projections of the substantia nigra 6.2.1. The nigro-thalamic projection 6.2.1.1. Electrophysiology and transmitter identity of nigro-thalamic projection 6.2.2. Nigro-brainstem projections 6.2.2,1. Electrophysiology and transmitters 6.2.3. Other nigral efferents 6.2.3.1. Nigro-amygdaloid projection 6.2.3.2. Nigro-raphe projection 6.2.3.3. Nigro-cortical projection 6.2.3.4. Nigro--locus-coeruleus projection 6.2.3.5. Nigro--cerebellar projection LP.N. 14/4--^

221

223 224 229 229 230 231 231 232 235 235 238 240 245 249 249 25O 251 251 252 252 252 258 258 259 260 260 262 262 263 263 265 271 271 271 271 271 271 272 272 272 272 272 273 273 274 274 274 277 278 279 279 279 279 279 279

222

A. DRAY

6.3. Afferent projections of the substantia nigra 6.3.1. The striato-nigral projection 6.3.1.1. Electrophysiology and transmitter identity 6.3.1.2. Identity of striato-nigral transmitter 6.3.2. Pallido-nigral projection 6.3.3. Raphe-nigral projection 6.3.4. Locus-coeruleus-nigral projection 6.3.5. Subthalamo-nigral projection 6.3.6. Nucleus accumbens-nigral projection 6.3.7. Cortico--nigral projection 6.3.8. Cerebello-nigral projection 6.4. Neuropharmacology of the substantia nigra 6.4.1. Dopamine in substantia nigra 6.4,1.1. DA-"autoreceptors" 6.4.2. NA in substantia nigra 6.4.3. 5HT in substantia nigra 6.4.4. GABA in substantia nigra 6.4.5. Glycine in substantia nigra 6.4.6. ACh in substantia nigra 6.4.7. Substance P in substantia nigra 6.4.8. Enkephalin in substantia nigra 7. Functional properties of basal ganglia components 7.1. Lesion studies 7.2. Stimulation studies 7.3. Correlations of motor performance and single cell activity 7.4. Functionally related changes by neurotransmitter manipulations in basal ganglia 7.4.1. Chemical lesions studies 7.4.2. lntracerebral injection studies 7.4.3. Tardive dyskinesia 8. Conclusions Acknowledgments References

Abbreviations Used in the Text ACh : ACHC: ADTN : BC: ChAT: CMPF: DA: DLH : DRN: 5,6,DHT: 5,7.DHT: EOS: EPSP: GPI: GPE: HD: 5HT: 5-HTP: 5HIAA: HVA: GAD: HRP: IPSP: IS: MFB: MRN: NSP: MD: 6-OHDA: PD: PSP: SN: SNC: SNR: SNL: STN : TOH : VA: VL:

acetylcholine aminocyclohexane carboxylic acid 2 amino--6,7 dihydroxy-l,2,3,4-tetrahydronaphthaline brachium conjunctivum cholineacetyl transferase thalamic center median parafaseicular complex dopamine D,L homocysteic acid dorsal raphe nucleus 5,6 dihydroxytryptamine 5,7 dihydroxytryptamine ethanolamine O sulphate excitatory postsynaptic potential internal segment of globus pallidus external segment of globus pailidus Huntington's Disease 5-hydroxytryptamine 5-hydroxytryptophan 5-hydroxyindole-acetic acid homovanillic acid glutamic acid decarboxylase horseradish peroxidase inhibitory postsynaptic potential initial segment median forebrain bundle median raphe nucleus nigro-striatal pathway t halamus-dorso-medial 6-hydroxydopamine Parkinson's Disease postsynaptic potential substantm mgra substantia nigra, pars compacta substantia nigra, pars reticulata substantia nigra, pars lateralis subthalamic nucleus tyrosine hydroxylase thalamus--ventroanterior thalamus--ventrolateral.

279 279 28O 282 283 284 285 285 285 285 286 286 286 288 288 288

289 290 291 292 292 292 293 295 296 30O 30O 302 303 3O3 305 3O5

MAMMALIANBASALGANGLIA

223

1. Introduction

M u c h uncertainty and inconsistency has surrounded the anatomical classification of the structures comprising the basal ganglia. A comprehensive account of this classification can be obtained from the review by Mettler (1968). Essentially the term "basal ganglia" has no precise limitation and has been considered by various authorities at various times to describe certain large subcortical nuclear masses in the upper forebrain. For example, these have included the caudate nucleus, the putamen (collectively called the striatum), the globus pallidus (or pallidum) and closely related structures such as the claustrum, substantia innominata, amygdaloid nuclear complex and zona incerta. Also functionally related are the subthalamic nucleus (corpus Luysii or body of Luys) and the substantia nigra. Common usage has, however, limited the term to include the striatum, the globus pallidus (the putamen and pallidus are in outdated nomenclature, referred to as the lenticular or lentiform nucleus), and the related subthalamic nucleus and substantia nigra (Carpenter, 1976a, b). In addition, however, Hassler (1978) suggests that the striatum should, in addition to the caudate and putamen, include parts of the striatal tissue lying basomedial to these structures called the "fundus striati" (the nucleus accumbens septi). Traditionally the basal ganglia have been regarded as being part of the extrapyramidal motor system; i.e., those central structures whose descending nerve tracts do not pass longitudinally through the medullary pyramids (which contain the bulk of the cortico-spinal tract). However, the central structures comprising the extrapyramidal system in this wider definition include, in addition to the basal ganglia, the mesencephalic and medullary reticular formation and the cerebellum (see, e.g., Bruggencate, 1975a). Also, nonpyramidal motor linkages such as the red nucleus and certain parts of the brainstem reticular formation receive direct cortical projections and give rise to rubro and reticulo-spinal fibers. Moreover, both anatomical (Russel and DeMyer, 1961) and electrophysiological studies (Patton and Amassian, 1960) have shown that the cortical origin of the pyramidal tract extends over more than only area four of the primary motor cortex, and that the pyramidal tract may supply collaterals to brainstem nuclei and other extrapyramidal structures (Wiesendanger, 1969; Bruggencate, 1975a). Pyramidal tract neurones are also connected to structures with either purely sensory function, such as dorsal column nuclei, or reflex function, such as interneurones mediating presynaptic inhibition in the spinal cord (Endo et al., 1963; Gordon and Miller, 1969; Lundberg, 1964). Thus, on these grounds separation of pyramidal and extrapyramidal systems appears arbitrary. Additionally, from functional aspects there appears to be no foundation for the concept of two independent motor systems. For example, after removal of the whole cortex giving rise to the pyramidal tract, the monkey can still project movements suprisingly accurately by vision and can avoid responses to tactile stimuli (Denny-Brown, 1962). Regarding precise function however, the basal ganglia have imposed considerable difficulties. Although they occupy a large volume of the subcortical parts of the brain, their exact role has thwarted detailed description. Neurological methods which depend on the production of precise experimental lesions have provided equivocal results (Denny-Brown, 1962), whereas clinical observations of basal ganglia disease also present difficulties because of diffuse and often widespread pathological pictures. Moreover, local lesions, such as vascular lesions or secondary tumors, while not uncommon, do not present easily recognizable symptoms (Martin, 1967). While diseases of the basal ganglia produce signs of excess motor activity such as tremor, involuntary movements, increased muscle tone, and pathological examination has revealed damage or destruction, it has none-the-less proved difficult to show which of the surviving structures were responsible for the involuntary and excess movements. However, Martin (1967), based on a comprehensive study of postencephalitic PD patients, concluded that the basal gangliar system, though playing a cooperative role with other postural systems, has a separate identity and a large measure of autonomy. Thus, in his opinion the basal ganglia and associated pathways form a system devoted to: (1) postural reflexes other than those of the anti-

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A. DRAY

gravity group (since patients with basal gangliar disease, however severe, retain their antigravity support), (2) organization of locomotion, initiated by controlled postural mechanisms and the elaboration of specialized motor relations to the environment by modification of the labyrinthine and body-righting reactions, (3) phonation and articulation by means of postural fixation of the tongue and larynx, and (4) control of facial expression (also swallowing, breathing, micturation and defaecation). In the widest functional sense, basal ganglia are involved in acts of "secondary automatisms" (Hassler, 1978), whereby learned or acquired skills such as walking and running can be performed without intentional or conscious control. Before such acts of mobility become secondary automatism, intentional activity, voluntary concentration of attention and repeated conscious efforts are necessary. Indeed, most motor actions, the reactive and mainly the spontaneous ones, are originally initiated by conscious intentions and do not take place without mental vigilance and conscious interference. The intensive investigation of basal gangliar structure and function which has occurred in the past few years has provided a great deal of additional information and some clarification of their role in brain function. This has necessitated modifying some traditional concepts and has also given an appreciation of the diversity of interconnections between brain areas considered to have little functional interrelation. These studies have also enhanced the understanding of the role of chemical neurotransmitters in basal gangliar pathways and identified dysfunctions of these systems in disease processes. In this respect, an appreciation of some of the basic requirements for understanding the relationship between neural subsystems is necessary. These include, e.g., the identification of the source and distribution of projections linking different components of the system; the functional signs of these links should be defined in terms of synaptic activation of the target elements. Finally, the synaptic activation should correlate with the actions of the presumed neurotransmitters in the projection. Our subsequent discussions will reveal that all of these requirements have rarely been met in describing the relationships amongst basal gangliar structures. Much of our recent information has derived from the use of new analytical techniques. For example, retrograde axoplasmic transport of proteins such as HRP or anterograde transport of radiolabelled amino acids has facilitated the identification of the source and terminations of nervous pathway. These techniques have circumvented the problems of interpreting neuronal degeneration studies in which axons of passage may also have been damaged (La Vail and La Vail, 1972; Cowan et al., 1972; Nauta et al., 1974). Immunohistochemical methods for neurotransmitter enzymes (e.g., TOH for DA) or the neurotransmitter itself (e.g., substance P) has allowed chemically specific neurones and their terminations to be identified (McGeer and McGeer, 1973). Additionally, the use of a variety of neurotoxic agents has allowed selective lesions of cell bodies and dendrites (kainic acid), specific monoaminergic neurones (60HDA, 5,7-DHT) or selective impairment of neurotransmitter release (tetanus toxin for inhibitory amino acids). Finally, the binding of labelled substances to synaptic membranes preparations has facilitated the localization of putative sites of action of neurotransmitters and their pharmacological antagonists (McGeer et al., 1978; Yamamura et al., 1978; Snyder and Bennet 1976). This article addresses itself, in a systematic discussion, to the physiology and pharmacology of the mammalian basal ganglia. In particular, i.t reviews the experimental evidence for neuronal interconnections, identity and synaptic actions of chemical transmitters and discusses the significance of these findings for the understanding of the part the basal ganglia play in brain function.

2. The Basal Ganglia and Neurological Disease Much of the impetus for studying basal ganglia properties has of course come from the neurological and pathological observations made during disease. As already mentioned, pathological lesions in the basal ganglia produce motor dysfunction manifested by abnormal involuntary movements, which include akinesia, chorea, athetosis, dystonia,

225

MAMMALIAN BASAL GANGLIA

ballism and tremor (Denny-Brown, 1962; Martin, 1967; Marsden and Parks, 1973; Marks, 1977). Because of the close correlation observed between the neurochemical and pathological profile, much attention has focused on the etiology and therapy of P.D. Thus, lesions and loss of pigmentation of the SN have been a common feature of P.D. (Tretiakoff, 1919; Hassler, 1938). Additional lesions are, however, also present in the striatum, globus pallidus, subthalamic nucleus, substantia innominata, locus coeruleus and reticular nuclei (Selby, 1968). The marked degeneration of DA neurones of the nigro-striatal pathway and the profound reduction of striatal DA and its metabolites provided a rational basis for the introduction of replacement therapy with L-DOPA (Birkmeyer and Hornykiewicz, 1961; Barbeau, 1969, 1978; Hornykiewicz, 1966; Curzon, 1977; Bernheimer et al., 1973; Cain and Sandler, 1970; Klawans et al., 1970). Since severe P.D. patients react more sensitively to L-DOPA it was suggested that the occurrence of supersensitivity of postsynaptic receptor sites compensated for the loss of DA transmission (Hornykiewicz, 1975; Klawans, 1973). Indeed, an increase in postsynaptic DA-receptor binding has been demonstrated in the caudate and putamen of postmortem P.D. brains, while presynaptic binding was reduced, presumably due to the loss of DA terminals (Lee et al., 1978). Chronic L-DOPA therapy, however, results in subsequent reduction of postsynaptic binding to normal values, suggesting a reduction of DA-receptor sensitivity (Lee et al., 1978; Reisine et al., 1977). These changes in receptor sensitivity may explain the "on-off" phenomenon frequently seen in patients on chronic L-DOPA therapy, and the lack of effectiveness of DA-receptor agonists in some P.D. patients (Marsden and Parks, 1976; Lieberman et al., 1976; Kartzinel et al., 1976; Gerlach, 1976). Besides DA, there are moderate to severe losses of other neurotransmitters in P.D. (see, e.g., Fahn et al., 1971; Lloyd and Hornykiewicz, 1974; Curzon, 1977) (see Tables 1-4). Post-mortem studies suggest striatal and pallidal ChAT activity is depressed (Lloyd et al., 1975; Reisine et al., 1977; Hornykiewicz, 1973) or unaffected (McGeer and McGeer, 1976a). This suggests additional losses of cholinergic neurones with a subsequent increase in "muscarinic receptor" binding due to denervation supersensitivity (Reisine et al., 1977). TABLE 1. NEUROTRANSMITTERSIN THE STRIATUM, AND CHANGESIN DISEASE

Transmitter Dopamine

Concentration per g wet tissue 74.56pg

% control in disease PD HC 29.3

Receptor binding % control PD HC

769(NS)6post synaptic 144

6pre-synaptic 64 1463 NT

Serotonin 70.35pg Noradrenaline 70.14pg

240 235.1

7377

Acetylcholine 52.7#g

1°38.1 14130 (CHAT) i o42.2 9NS (GAD)

7NC

GABA

t 1172.2/~g

a46.8 (CHAT) t o74.8 (GAD)

Glycine Glutamate

1157.1pg 11919.6ttg

NT NT

NT NT

NT NT

Substance P

1260ng

NT

179 (NS)

NT

Enkephalin

12918ng

NT

370

NT

Source of transmitter Nigro-striatal pathway

1357

438 Raphe (mainly DRN) 4NS Locus coeruleus (fl-receptor) 450 Intrinsic and from CM=PF complex 4NS Intrinsic and in strionigral, strio--pallidal pathway NT Intrinsic t550 Intrinsic and corticostriatal pathway NT Cell bodies of strionigral, strio-pallidal pathway NT Cell bodies of striopallidal pathway

From: 1Cuello et al., 1978.2Curzon, 1977. 3Emson (personal communication).4Enna et al., 1976b. 5Fahn, 1976. 6Lee et al., 1978. 7Lloyd and Hornykiewicz,1974. aLioyd et al., 1975. 9Lloyd et al., 1977. t°McGeer and McGeer, 1976a. ltPerry et aL, 1971. 12Pollard et al., 1978. 13Reisine et al., 1978. 14Reisine et al., 1977. 15Yamamura (personal communication).NC, no change. NS, not significant. NT, not tested. PD, Parkinsons disease. HC, Huntingtons chorea.

226

A. DRAY TABLE 2. NEUROTRANSMITTERS IN THE GLOBUS PALLIDUS AND CHANGES IN DISEASE

Transmitter

Concentration per g tissue

"'i, control in disease PD HC

Receptor binding PD HC

Dopamine

5766 ng

636

NT

14NC

1562

Serotonin

5301 ng

657

1°60.5

~4NC

425

Noradrenaline Acetylcholine

NT 14NC

454 '*50 "*NC

13178,ag 131550/~g °448 ng

t231.8 (GAD) NT NT 248.1

I'*NC

Glycine Glutamate Substance P

6167 1116.8 (CHAT) t~35.2 (GAD) NT NT NT

NT 1633.6

GABA

s69 ng 70.25 pmol/ #g protein s586 pg

NT NT NT

NT INS NT

Enkephalin

876 ng/mg protein NT

350

NT

NT

Source of transmitter Terminals and in nigrostriatal fibers Terminals of raphe-pallidal fibers Unknown Intrinsic? Unknown'? Cell bodies and terminals of stric~pallidal fibers Unknown Unknown Cell-bodies of pallidonigral pathway and fibers of striato-nigral pathway Terminals of strio-pallidal fibers

From: ~Beaumont et al., 1979. 2Cueilo et al., 1978. 3Emson (personal communication). 4Enna et al., 1976b. SFahn, 1976. 6Fahn et al., 1971.7Hoover et al., 1978. SHong et al., 1977a. 9Kanazawa and Jessell, 1976. 1°Lloyd and Hornykiewicz, 1974. l lLloyd et al., 1975. 12McGeer and McGeer, 1976a. 13Perry et al., 1971a,b. 14Reisine et al., 1977. :SReisine et al., 1978.16Wastek and Yamamura, 1978. NC, no change. NS, not significant. NT, not tested. PD, Parkinsons disease. HC, Huntingtons chorea. TABLE3. TRANSMITTERSIN THE SUBTHALAMICNUCLEUS Transmitters

Concentration per g tissue

':~ocontrol in disease PD

Source

Dopamine Serotonin Noradrenaline Acetylcholine (CHAT) GABA (GAD)

40.05/tg 611.2 ng/mg protein 20.48/~g 127.5 nmols ACh/hr/ mg protein s249/tmols/hr/g protein

NT NT 287.5 NT

Unknown Possibly raphe terminals Unknown Unknown

NT

Glycine Glutamate Substance P

NT NT 3315 ng

NT NT NT

Terminals of pallid,> subthalamic fibers Unknown Unknown In fibers, source unknown

From: lFahn, 1976. 2Farley and Hornykiewicz, 1976. 3Kanazawa and Jessell, 1976. '*Lloyd, 1975. SMassari et al., 1976. 6palkovits et al., 1974. NT, not tested. PD, Parkinson's disease. O n the other hand, the deficiency in nigro-striatal D A transmission itself is considered to p r o d u c e an overactivity of striatal cholinergic neurones, and thus explain the efficacy of anticholinergic drug therapy in P.D. (Yahr and Duvoisin, 1968). Alternatively, cholinergic overactivity has been been speculated to result from sprouting of cholinergic neurones to replace the lost DA-terminals (Spehlman and Stahl, 1976). In view of the receptor binding d a t a the denervation supersensitivity hypothesis appears a more plausible explanation for striatal cholinergic hyperactivity in P.D. Significantly reduced G A D activity has been reported in P.D. both in the striatum, globus pallidus and SN (McGeer e t al., 1971; Lloyd and Hornykiewicz, 1973; M c G e e r and McGeer, 1976a). This appears to be accompanied by a decrease in 3 H - G A B A binding in the SN (Lloyd e t al., 1977) and m a y result from a loss of postsynaptic D A neurones. G A B A binding in the pallidum and striatum, however, is n o r m a l (Reisine e t al., 1977). L o n g - t e r m treatment with L - D O P A (1 yr or more) restores G A D activity to within the n o r m a l range (Lloyd and Hornykiewicz, 1973), suggesting that striatal and pallidal G A D - c o n t a i n i n g neurones are u n d a m a g e d and m a y normally operate under the trophic influence of the DA-ergic system (Hornykiewicz e t al., 1976). Additionally, there is m o d e r a t e to severe loss of N A in P.D. brains particularly from the locus coeruleus, striatum, pallidum, SN and the nucleus paranigralis-parabrachialis

s 1.02/~g s0.23/~g

i 1.29/~g

12546 #g

1,172.7 #g 12884.1 #g ~884.8 ng

60.66 ng/mg protein

Serotonin Noradrenaline

Acetylcholine

GABA

Giycine Glutamate Substance P

Enkephalin

4,

NT

NT NT NT

1121.6 (GAD)

925 (CHAT)

'40 250

215

350

t 2NC 12NC ~16

t 125.8 (GAD)

NT

NT s200

SNC

% control in disease PD HC

NT

NT NT NT

t°31.4

NT

NT NT

NT

NT

NT NT NT

"183

13NC

NT NT

l+NC

Receptor binding ' % control PD HC

NEUROTRANSMITTERS IN THE SUBSTANTIA NIORA, AND CHANGES IN DISEASE

Cell bodies of NSP, nigral dendrites and SNR cells Terminals of raphe projection Terminals (maybe of locus cocruleus projection)? Cell bodies? Intrinsic and terminals of unidentified afferents Intrinsic and terminals of strio-nigral, pallido-nigral pathway Intrinsic? Intrinsic? Terminals of strio-nigral pallido-nigral pathway. Cell bodies and fibers

Source of transmitter

From: ~Cheney et al., 1975. 2Curzon, 1977. 3Emson (personal communication). +Enna et al., 1976b. SFarley and Hornykiewicz, 1977. 6Hong et al., 1977a. 7Kanazawa et al., 1977a. SLloyd and Hornykiewicz, 1974. 9Lloyd et al., 1975. t°Lloyd et al., 1977. ttMcGcer and McGeer, 1976a. 12Perry et al., 1973. 13Wastek and Yamamura, 1978. t+Reisine et al., 1978. NC, no change. NS, not significant. NT, not tested. PD, Parkinsons disease. HC, Huntington's chorea.

s0.49 gg

Dopamine

Transmitter

Concentration per g wet weight

TABLE

r.

Z

I-'

w

'7

x

228

A. DRAY

pigmentosus (topographically and morphologically related to the caudal SN) (Farley and Hornykiewicz, 1976; Lloyd and Hornykiewicz, 1974). Reductions of 5HT and its metabolite 5HIAA also occur in several regions, including striatum, pallidum, thalamus and SN (Lloyd and Hornykiewicz, 1974). This may result from impaired 5HT synthesis in the midbrain raphe (Lloyd, 1977). Indeed P.D. patients with low CSF 5HIAA compared with HVA levels appear to respond less readily to L-DOPA therapy (Gumpert et al., 1973). However, administration of the 5HT precursor 5HTP sometimes reduces P.D. symptoms, especially tremor (Sano and Taniguchi, 1972), but may also excacerbate the symptoms (Chase et al., 1972). For a more detailed discussion of the role of monoamines in clinical dyskinesias see Fahn et al. (1971). Recent advances have also been made in understanding the etiology of HD, a complex neurological disorder characterized by severe choreiform movements and progressive dementia (see Bruyn, 1968, for comprehensive clinical description). Marked neuropathalogical changes, characterized by severe neuronal loss, occur in the striatum, pallidus and subthalamic nucleus (also, there are marked cell losses in the cerebral cortex) (Lange et al., 1976). These are accompanied by a decrease in the activity of GAD (loss of GABA neurones), ChAT (loss of cholinergic neurones) and a reduction in GABA concentration in these areas and in the SN (Wastek and Yamamura, 1978; Perry et al., 1973; McGeer et al., 1973; Bird and Iversen, 1977; Bird et al., 1973; Hiley and Bird 1974; Stahl and Swanson, 1974). There is also a reduced GABA concentration in CSF samples of HD patients (Enna et al., 1977). In some patients an elevated striatal 5HT concentration has been measured (Bernheimer and Hornykiewicz, 1973). Receptor-binding studies in post-mortem HD brain reveal a reduction in cholinergic muscarinic and serotonin receptors in the striatum and pallidus (Enna et al., 1976b; Enna et al., 1976c; Hiley and Bird, 1974; Wastek et al., 1976; Wastek and Yamamura, 1978), unchanged GABA-binding in these regions, but an increase in GABA receptors in the SN (Enna et al., 1976b). These observations suggest that 5HT-receptors normally impinge upon cholinergic or GABA neurones, and that degeneration of GABA neurones of the strio-nigral pathway results in a denervation supersensitivity in the SN, revealed by an increase in the number of GABA binding sites (Enna et al., 1976b). The reduction of cholinergic receptors may also explain why therapy of HD with cholinergic agents has been of limited success (Kalawans and Rubovits, 1972a; Tarsy et al., 1973; Aquilonius and Sjostron, 1971; Walker et al., 1973). In some patients, however, ChAT activity is normal but cholinergic receptors are still reduced. This suggests that postsynaptic neuones, probably GABA-ergic, may be the site of the primary lesion and that HD may be essentially a GABA-deficiency syndrome (Hiley and Bird, 1974). Therapy with GABA-mimetics has, however, been of limited success, possibly because of insufficient cerebral drug penetration or the occurrence of undesirable side effects (Shoulson et al., 1975; Shoulson et al., 1976; Barbeau, 1973). Alternatively, changes in the content of brain phospholipids or their metabolites in HD may influence the actions of GABA-mimetic agents (Lloyd and Davidson, 1979). Also, clinical studies suggest that benzodiazepines may be effective in alleviating some of the motor abnormalities in HD (Farrell and Hoffmann, 1968; Peiris et al., 1976). Interestingly, the benzodiazepines are considered to exert their actions through GABA-linked processes (e.g. see Guidotti, 1978; Guidotti et al., 1979), and a decrease in the number and affinity of benzodiazepine receptor binding sites has been demonstrated in the striatum of HD brain (Reisine et al., 1979). Therapy of HD has also been directed towards blocking DA-ergic activity with neuroleptic drugs (see Bruyn, 1968; McLellan et al., 1974), suggesting an over-activity of DA-transmission or DA-receptor hypersensitivity in this disease (Klawans, 1970). Indeed, DA agonists exacerbate the symptoms of HD. However, neurochemical studies suggest that striatal DA concentrations are normal but DA turnover may be either unchanged or decreased as judged from CSF, HVA estimations (Hornykiewicz, 1966; Curzon et al., 1972). On the other hand, others show an increase in TOH activity in the SN and a decrease in striatal DA concentration in HD, compatible with an increase in nigro-

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striatal DA turnover (Bird 1976; Bernheimer and Hornykiewicz, 1973). Moreover, receptor-binding data reveals a reduction in neuroleptic binding (to presumed DAreceptors) in the striatum and pallidum, but not in the SN (Reisine et al., 1978a), and this appears compatible with increased DA-transmission. This study also showed a dramatic reduction in neuroleptic binding in the frontal cortex, but it is unclear whether this reflects changes in dopamine or serotonin receptors. The development of an animal model for HD, based on the neurological, cytological and neurochemical similarities of striatal lesions with kainic acid and those observed in HD (Coyle and Schwarcz, 1976; McGeer and McGeer, 1976b; see Section 7.4.1) has suggested the additional involvement of striatal glutamate mechanisms in this disease (Olney and deGubareff, 1978). Indeed, receptor binding studies with 3H-kainic acid (presumably to glutamate receptors) reveals a significant decrease in HD (52~ of normal in caudate and 479/0 in putamen) (Beaumont et al., 1979). These losses may result from damage of the striatal target neurones of the cortico-striate pathway, which is considered to be glutamatergic (see Section 3.2.1.2). Further complexities in the etiology of HD have been the finding that substance-P concentrations are depleted in the SN, probably due to loss of neurones in the striatum and globus pallidus (Kanazawa, et al., 1977). Also, there are marked reductions in the activity of angiotensin converting enzyme (converts angiotensin I to angiotensin II) in the striatum and globus pallidus (Arregui et al., 1978; Emson, 1979). The significance of these and other polypetides (e.g. vasoactive intestinal polypeptide, cholecystokinin) in basal gangliar function is not presently understood. 3. The Striatum 3.1. MORPHOLOGY The morphological characteristics of basal gangliar structures will be discussed only to give a representation of the prevailing views. A comprehensive account of the cytoarchitecture may be found in a number of more extensive articles devoted to this subject (e.g., Nauta and Mehler, 1966; Mettler, 1968; Carpenter, 1976a, b; Fox and Rafols, 1976; Nieuwenhuys, 1977, Hassler 1978). There are, however, two 9utstanding general features of basal ganglia circuitry which have been emphasized: (1) the topographical arrangement of projections and inputs, and (2) the reciprocation of neuronal pathways forming "neuronal loop pathways" (e.g. see Webster, 1975; Nieuwenhuys, 1977). The striatum, by far the largest component of the basal ganglia, is considered as a single anatomical and functional entity, in which the caudate and putamen are separated by the internal capsule, but only in primates. Cytologically, the caudate and putamen are considered to be identical with densely packed cells showing no laminations or specialized arrangements. Certain parts of the striatum have, however, been described as being divided into cellular areas such that within each area there is a patterning of organization comprising clusters or aggregations of cells (Kemp and Powell, 1971a; Mensah, 1977). Also, arrangements of cells in highly branched mosaics as well as in ring formation with dendritic bundles forming circumscribed dendritic fascicles have been described (Scheibel and Scheibel, 1973; Chronister et al., 1976; Edley et al., 1978). Synapses are also present in groups (Tennyson and Marco, 1973) and these arrangements may in fact represent sites for topographical projections or inputs (Goldman and Nauta, 1977; Royce, 1978a). There appear to be at least four types of striatal nerve cell (Mori, 1966; Kemp and Powell, 1970; Fox et al., 1971a,b; Rafols and Fox, 1975; DiFiglia et al., 1976; Hassler, 1978), based on their size and presence of dendritic spines: (1) giant neurones or large pyramidal "aspiny" neurones (0.79/0) considered to be output neurones; (2) large spindle shaped "spiny" neurones, some of which send axons to the SN (4-69/0); (3) smaller "spiny" neurones; considered to be interneurones (909/o), corresponding to medium sized neurones with smooth dendritic trunks but with main dendrites covered with robust pedunculated spines; and (4) dwarf cells (Cajal, 1911) considered to be true Golgi II cells (short

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axoned, almost 1~o). Though axons of spiny neurones were considered to be short and to ramify mainly within the confines of the dendritic field of the parent cell (Kemp and Powell, 1971a, b; Fox et al., 1971a), more recent observations suggest that some 30-509/0 of striatal neurones are indeed output cells, many being the medium sized spiny striatal neurones (DiFiglia et al., 1976; Grofova, 1975; Bunney and Aghajanian, 1976; Kocsis et al., 1977; Somogyi and Smith, 1979) (see Section 6.3.1). As many as nine types of striatal synapses have been described (see Hassler, 1978). Three types (I, III and IV) forming axo-spinous connections on spiny neurones are predominant. Type I boutons derive from nigro-striatal fibers, type III from somatosensory cortex, and type IV from the parafascicular or centre median nuclei of the thalamus. Axo-somatic contacts are usually made by type II, VI and VII synapses. The source of type II and VI boutons is unknown (possibly amygdaloid complex, pallidum or raphe), but type VII appears to derive from the cerebral cortex. Axon collaterals of large striatal neurones may account for type V boutons, but type IX synapses appear to be from intrinsic neurones, while type VIII may originate from striatal dwarf cells. Most striatal fibers are of fine caliber (0.3-1.6/~m) with poor myelination. Afferent fibers, together with collaterals from axons of intrinsic cells, form a dense felt-like plexus completely investing the constituent neurones and their processes (Adinoffi and Pappas, 1968; Verhaart, 1950). Striatal efferent fibers form a dense fine "radial fiber" system in the caudate and putamen. These fibers converge on the globus pallidus like the spokes of a wheel, and some continue by way of the "comb bundle system" through the cerebral peduncle into the SN (Wilson 1914; Papez, 1941; Fox and Rafols, 1975; Fox et al., 1975). The radial fibers undergo a reduction (about 6090) in caliber as they traverse the globus pallidus, but the significance of this change is not understood (Fox et al., 1975; see also Section 4.2.1). 3.2. STRIATAL AFFERENT PROJECTIONS Some insight into the functional differentiation of the striatum may be obtained by calculating the proportions of each of the nine types of synapses (Hassler, 1978). Hassler

FIG. 1. Schematic representation of connections of the striatum. No indication of the respective density of projections is intended. Key: CX, cortex; thalamic nuclei, CM-PF, centromedianparafascicular complex; CL, central lateral intralaminar nucleus; VA, ventroanterior; DM, dorsomedial thalamus; AM, amygdala; AC, nucleus accumbens; LC, locus coeruleus; RF, reticular formation; GPI, internal pallidal segment; GPE, external pallidal segment; SNC, substantia nigra, pars compacta; SNR, substantia nigra, pars reticulata; DR, dorsal raphe nucleus.

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thus suggests that the caudate receives its main input (35?/o) from the centre median nucleus of the thalamus, 16~o from the ipsilateral SN and 13Yo from the cerebral cortex, indicating that the caudate is in some respects thalamus orientated. The putamen however appears somewhat cortex orientated and receives a greater number of terminals from the cortex (33~o), about 16~o from the centre-median nucleus and !6~o from the SN (see Electrophysiology section 3.2.1b). Connections of the striatum are summarized in Fig. 1. 3.2.1. Cortico-striatal projections Probably the most extensive input to the striatum is that from the neocortex, with virtually all regions projecting via fine axons in a topographically ordered fashion. For example, fibers from the frontal cortex end in the head of the caudate, those from the orbital cortex end in the ventral parts, while those from the dorso-lateral cortex in dorsal regions (Webster, 1961, 1965; Glees 1944; Carman et al., 1963; Nauta, 1964; Carman et al., 1965; Kemp and Powell, 1970, 1971c, d; Kunzle, 1975; Goldman and Nauta, 1977; Jones et al., 1977; Kunzle and Akert, 1977). The organization of these projections is more complex in primates because of the more extensive development of the temporal lobe (Kemp and Poweli, 1970). There is, however, considerable overlap of terminal fibers in all dimensions, suggesting that no part of the striatum is under the sole influence of one functional area of the neocortex. However, projections from the sensorimotor cortex are, e.g., more substantial than those from the visual cortex and indeed some projections from primary motor areas are well localized (Garcia-Rill et al., 1979b; Tanaka et al., 1979). Also, projections from the sensorimotor areas are bilateral, though these are sparse in primates where they arise principally from supplementary motor area and from area five (Kemp and Powell, 1970; Carman et al., 1965; Jones and Powell, 1969). In primates, area four appears to project ipsilaterally and contralaterally predominantly to the putamen (Kunzle, 1975). The cortico-striate projections, like other striatal afferents, end in patch-like clusters, primarily on the proximal segments of the dendritic spines of spiny striatal neurones (Fox et al., 1971a; Kemp and Powell, 1970; 1971c, d; Adinolfi and Pappas, 1968; Hattori et al., 1979a). These boutons contain round vesicles and have been suggested to be morphologically typical of excitatory synapses (Hattori et ai., 1979a). 3.2.1.1. Electrophysiology o f striatal neurones Before describing the electrophysiological studies confirming cortico-striatal projections it is appropriate to discuss some basic properties of. striatal neurones. Many workers have observed that there is a low level of spontaneous activity in the striatum which may result from unique accommodation of striatal neurones as well as from synaptic regulation of spike activity (Marco et al.; 1973a; Purpura and Malliani, 1967; Hull et al., 1970). On the other hand, most striatal afferents have been suggested to be excitatory (Buchwald, et al., 1973; Hull et al., 1973), whereas intrinsic activity appears mainly inhibitory (Marco et ai., 1973a). Thus, in the absence of external drive, most cells appear to be in a state of tonic inhibition. Though little attention has been focused on the intrinsic biophysical properties of caudate neurones, Sugimori et al. (1978) recently reported a series of experiments in barbiturate anesthetized cats, in which electrical constants of neurones were measured. The cells studied received monosynaptic EPSPs from the C M P F or SN and were identified as medium sized spiny neurones. Making certain assumptions concerning the spatial relationships of soma and dendrites, these authors calculated values for membrane input resistance and membrane time constant (16.5 Mf~ and 11.3 msec respectively), and suggested that although the passive membrane resistance of caudate neurones was higher (78,000 fl cm 2) than that reported from other central neurones, it would allow for effective electrotonic spread of current generated by synaptic activity in dendritic regions to the axonal trigger Zone. Also, they suggest that the low level of activity in caudate neurones was unrelated to intrinsic membrane properties, but was more likely to result from

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specific features of the temporal and spatial interactions of their opposed synaptic inputs. Moreover, the membrane properties (long time-constant) of spiny neurones would have a smoothing influence on diverse synaptic bombardment, and thus these neurones appear to be particularly well suited for relatively long-term averaging of excitatory inputs. 3.2.1.2. Electrophysiology and transmitter identity o f the cortico-striatal projection Electrical stimulation of many parts of the cortical surface (e.g. orbito-frontal cortex, postsygmoid gyrus) evoked a complex series of potentials in the caudate nucleus, usually consisting of a larger positive component followed by a more prolonged negative wave (Albe-Fessard et al., 1960a; Liles, 1973, 1975; Blake et al., 1976), suggesting that large groups of cortical neurones respond in a uniform fashion to electrical stimulation. No responses, however, were obtained in striatum following stimulation of the anterior lateral gyrus, post-ectosylvian or occipital cortex, while longer latency responses were obtained following~contralateral anterior sigmoid stimulation (Blake et al., 1976). Evoked potentials also showe,d mediolateral and anterior-posterior topography (Blake et al., 1976; Liles 1973, 1975), though the orbito-frontal and motor-sensory areas project more predominantly to anterior caudate, whereas all portions of the suprasylvian gyrus project more posteriad. Blake et al. (1976) also concluded that the contralateral cortico-striatal projections ran through the subcallosal fasciculus, whereas the ipsilateral pathway took a course both through the internal capsule and the subcallosal fasciculus. Earlier extracellular studies suggested only weak activation of caudate neurones by cortical stimulation (Rocha-Miranda, 1965) with some evoked depression (Albe-Fessard et a l . , i O 6 0 b ; Buchwald et al., i973; Sedgwick and Williams, 1967; Liles, 1974), while intracellular recordings showed three types of response; EPSPs, EPSP-IPSP sequences, and IPSPs alone (Buchwald et al., 1973; Hull et al., 1970). However, the EPSP-IPSP sequences appeared to be the predominant response (Hull et al., 1970, 1973; Buchwald et al., 1973; Kocsis et al., 1977a; Garcia-Rill et al., 1979b). Fuller et at. (1975) suggested, since they observed no pure IPSPs, that the EPSP was produced by activation of excitatory inputs, while the following PSPs were generated internally and mediated by interneurones which project onto each other. Also significant in earlier studies was the presence of prolonged EPSPs from which spike activity was difficult to generate (e.g. Purpura et al., 1967). Indeed Marco et al. (1973a) emphasized that spike responses were suppressed following electrode impalement of a neurone. EPSPs could, however, be recorded for several minutes, even in cells which had been irreversibly damaged. Purpura (1975) reasons that under these circumstances it would be hazardous to interpret extracellular data, since failure to detect discharges of caudate neurones would not exclude synaptic activation of "silent" neurones by subthreshold EPSPs. The relatively long duration EPSPs in caudate neurones have been considered to result from the release of a long-acting depolarizing agent or the absence of hyperpolarizing agents (Hull et al., 1970). Indeed, such changes may function to set the membrane potential near to firing threshold for fairly long periods, so that excitatory inputs, ordinarily ineffective, might subsequently fire the cell. This mechanism would, e.g., be useful for timing and sequencing behavioral responses in the presence of relatively constant stimulus inputs, such as in a delayed response behavioral paradigm (Divac, 1968). Intracellular injections of hyperpolarizing or depolarizing current confirm that cortical evoked potentials were in fact genuine EPSPs with a reversal potential around - 2 mV (Kocsis et al., 1977a) (see Fig. 2). However, these authors found it was generally difficult to provide adequate measures of reversal potential, probably due to technical limitations of passing adequate intracellular current (see also Marco et aL, 1973a) and of electrotonic spread of injected current to distal dendritic sites where cortico-striate terminals impinge. Depolarizing current injections also produce rhythmic sequences of depolarization in striatal neurones which were considered to be similar to "spindle" activity seen in extracellular studies (see Buchwald et al., 1967, 1973). Some cortico-striatal activation occurs after long latency and though compatible with

233

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FIG. 2. The effects of intracellular polarization on cortical (CX, A-D) centromedian parafasicular thalamic (CMP, E-H) and substantia nigra (SN, l-L) induced depolarization of cat caudate neurones. The top row shows the control responses. In B, F, J, the amplitude of the responses are increased with the passage of 4.8, 7.2 and 2.4 nA hyperpolarizing pulses (100 msec), respectively. In C, the CX depolarization is reversed to a hyperpolarizing response with the passage of 5.6 nA depolarizing current, while depolarization levels of 2.4 nA and 4.6 nA in G and K respectively, greatly reduce the amplitude of the responses. D-L are graphical representations of response amplitude (mV in ordinate) as a function of polarizing current (nA in abscissa). The small arrows indicate the onset of three shock pulse trains. The changes in amplitude and rise times with current injection suggest that the evoked depolarizing potentials are EPSPs. (From Kocsis et al., 1977: reproduced with permission.)

antidromically measured conduction times, may have been due to indirect activation via a corticothalamic pathway (Cherubini et al., 1979) or activation of polysynaptic circuits in the striatum. Indeed, such polysynaptic circuits have been shown to operate within the caudate as determined by microstimulation experiments where the recording and stimulating electrodes are positioned in close proximity (1.5 mm apart) (Marco et al., 1973b). These experiments reveal that in a variety of preparations (anesthetized, unanesthetized or isolated caudate preparations) variable latency (average 10 msec), negative field potentials occur with single unit spikes being evoked on the falling phase of the peak potential. Spontaneous cell-firing was also arrested for prolonged periods (150-200 msec), suggesting that this intrinsic phenomenon may account for the long-lasting unresponsiveness of neurones following external stimulation (cf. Fuller et al., 1975). Furthermore, the low degree of spontaneous activity in caudate neurones was suggested to result from their maintenance under conditions of marked quiescence by relatively high resting membrane potentials (70 mV or more) (Marco et al., 1973a). Thus, caudate neurones may normally be in a state of relative hyperpolarization (Hull et al., 1970). There is unanimity in the fact that caudate neurones are monosynaptically activated by cortical stimulation (Rocha-Miranda, 1965; Buchwald et al., 1973; Hull et al., 1973; Liles, 1974; Kitai et al., 1976a; Kitai et al., 1976b; Kocsis et al., 1977a; Vander Maelen et al., 1978a). These fibers appear to be independent of cortico-spinal or cortieo-bulbar systems (Blake et al., 1976; Kitai et al., 1976b). However, cortical projecting cells identified antidromically by caudate stimulation and by retrograde HRP transport appear to be restricted predominantly to the medium size pyramidal cells in cortical layer III,

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though some are also in layer V and VI (pericruciate cortex) (Kitai et al., 1976b). Cortico-spinal and cortico-bulbar cells, on the other hand, appear to be mainly in layer V (Berrevoets and Kuypers, 1975; Bishop et al., 1976; Coulter et al., 1976; Naito et al., 1969) and cortico-thalamic neurones in layers V and VI (Romagnano and Maciewicz, 1975). Cortico-striatal fibers appear slowly conducting (0.8-1 m/sec) (Spencer, 1976; RochaMiranda, 1965; Liles, 1974; Kitai et al., 1976b) and project to medium size spiny neurones in the caudate which have long axons of undetermined destination, and are possibly output neurones (Kocsis et al., 1977a). These cells also appear to receive converging inputs from the CMPF nucleus and the ipsilaterai SN (Hull et al., 1973; Kocsis et al., 1977a), but not from the VL thalamus or basilar pons (Kitai et al., 1976b). Indeed, the paired stimulation experiments of Hull et al. (1973) suggested that the cortical stimuli tended to be prepotent and regulate the response to other stimulus sites (see also Vander Maelen et al., 1978a). Thus, the cortically evoked test EPSPs or IPSPs were markedly attenuated if they fell in the range of the cortical evoked conditioning IPSP. However, when the test stimulus was applied to the cortex and conditioning stimulus to another site (CMPF or SN) there was little attenuation of the total cortical EPSP-IPSP (see Figs 3 and 4). Interestingly, target cells of the cortico-striatal projection were considered unlikely to be output neurones since very few responded to antidromic stimulation of the SN or entopeduncular nucleus (Liles, 1974; Fuller et al., 1975; Kitai et al., 1975; Kocsis et al., 1977a). However, this aspect of striatal efferents will be discussed in Section 3.2.3.1. The general consensus, therefore, from the electrophysiological data suggests that the cortical input to the striatum is both monosynaptic and facilitatory. Compatible with this is the fact that lesions of the frontal cortex produces a marked slowing of caudate neuronal firing (Garcia-Rill et al., 1979). Though earlier studies (McLennan, 1964) did not reveal the identity of the neurotransmitter in this pathway they suggested that it acted to prevent ACh or DA release. More recent evidence strongly suggests the involvement of an excitatory amino acid. Thus pharmacological studies (Spencer, 1976) showed that cortical evoked excitation of rat caudate neurones could be reversibly suppressed by

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FIG. 3. Prepotency of the cortex illustrated by suppression of the centre median (TH) evoked EPSP by a conditioning cortically (CX) evoked IPSP. The top left shows an EPSP-IPSP sequence evoked by cortical stimulation alone while TH stimulation evoked a "pure" EPSP (top middle and right). When the two stimuli were paired so that the cortical stimulus preceded the TH stimulus the "pure" EPSP response was suppressed (bottom left). Even when the intensity of TH stimulation was increased (10-15 V), cortical stimulation produced a strong inhibition of the TH, EPSP (bottom right). The arrows show the point at which stimulation occurred. All traces are averages of ten consecutive responses. (From Hull et al., 1973; reproduced with permission.)

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Fro. 4. Cortical dominance is also shown in this figure where substantia nigra stimulation (BS) enhanced the EPSP response to a cortical stimulus (left top and bottom) but a preceding cortical stimulus inhibited the EPSP evoked by nigral stimulation (right top and bottom traces). The arrows show the point at which the stimulus was delivered. All traces are averages of ten consecutive responses. (From Hull et al., 1973; reproduced with permission.)

the electrophoretic administration of the glutamate antagonist glutamic acid diethylester (GDEE). Though no other control agonists were used in this study, GDEE was also shown to suppress neuronal excitation produced by electrophoretic aspartate and DLH. Spencer (1976) concluded, however, that either glutamate or aspartate was the corticostriatal neurotransmitter. Support for this proposition has come from a number of neurochemical studies. Thus the striatum is high in 3H-kainic acid binding sites (suggesting the presence of glutamate receptors) (Simon et al., 1976; Beaumont et al., 1979), while lesions of the cortex result in a significant reduction of striatal kainic acid binding, glutamate concentration and high affinity glutamate uptake with little effect on other striatal neurotransmitter systems such as GABA, ACh, or DA (McGeer et al., 1977; Divac et al., 1977; Kim et al., 1977; Henke and Cuenod, 1979). Such lesions also reduced high affinity glutamate uptake in the frontal cortex. 3.2.2. The thalamo-striate projection This projection arises mainly unilaterally from the intralaminar thalamic nuclei with the majority of fibers originating in the CM-PF complex, traversing the internal capsule and projecting topographically to the putamen and to the body of the caudate (Powell and Cowan, 1954, 1956, 1967; Cowan and Powell, 1955; Kemp and Powell 1971c, d; Royce, 1978a, b; Jones and Leavitt, 1974). There appears to be a dorsal-ventral topographic relationship between the CM nucleus and its projection to the caudate and putamen (Royce, 1978a). Also, fibers from the CM are densest, while those from the PF are sparse (Royce, 1978b; Kuo et al., 1978). Neurones both in the VA (diffusely scattered) and the MD (mainly caudal) thalamic nuclei also project to the striatum, while additional projections are provided from small cells lying medially within the central lateral intralaminar nucleus (CL). Interestingly, these CL cells receive a projection from the deep layers of the superior colliculus while larger cells of the CL receive inputs from the spinothalamic tract and project to the somatic motor cortex (Albe-Fessard et al., 1971; Jones and Leavitt, 1974). These observations also question the suggestion that it is only the striatally projecting cells of the CM which send sparse collaterals with diffuse distribution to the cerebral cortex (see, e.g., Carpenter, 1976a, b; Rasminsky et al., 1973). Electron microscopic evidence suggests that the thalamo-striatal fibers terminate on the dendritic spines of spiny striatal neurones (Fox et al., 1971a; Kemp, 1968), and that some of these cells have long axons ( -~2 mm, not typical Golgi II neurones) whose destination is unknown (Kocsis et al., 1977a). 3.2.2.1. Electrophysiolooy of thalamo-striatal projection The earliest electrophysiological experiments in the basal ganglia had already established that the striatum participated in the generalized electrographic effects produced by

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FIG. 5. Characteristics of EPSPs evoked in a caudate neurone by low-frequency stimulation in the medial thalamus. The first stimulus of the repetitive series elicited a prominent long duration EPSP which increases in magnitude, after the second stimulus and may evoke a spike potential (bottom traces A and B, which are continuous reeords). The top traces in A and B show the accompanying recruiting response in the motor cortex. However, the maximum EPSP amplitude of this caudate neurone is attained prior to the full development of the cortical surface recruiting negativity. (From Purpura and Malliani, 1967: reproduced with permission.)

stimulation of the medial and intralaminar thalamic nuclei (see Purpura, 1975; Frigyesi, 1971). Subsequently, Purpura and Malliani (1967) and others (Hull et al., 1973; Buchwald et al., 1973) showed that repetitive low-frequency stimulation of the medial thalamus (CM-PF nuclei) elicited long latency (15-20 msec) EPSPs in the caudate. These effects were facilitated by subsequent stimuli during which neuronal spiking could be evoked (Fig. 5). Prominent EPSPs were also evoked in the putamen with repetitive spike discharges (Malliani and Purpura, 1967). These cells could also be driven by caudate stimulation but with somewhat longer latency and with shorter duration EPSPs. Such observations were confirmed by extracellular studies (Rasminsky et al., 1973) in which antidromic latencies of thalamo-striatal neurones were shorter (0.8-3.4 msec) than those reported by Milliani and Purpura (1967). Although the effects of thalamic stimulation were accompanied by recruiting responses in the motor cortex (Malliani and Purpura, 1967; Hull et al., 1973: Buchwald et al., 1973)

lOOmsec FIG. 6. Lack of effects of acute rostral cortex ablation (all cortex rostral to the head of the caudate) on intracellularly recorded synaptic events in caudate neurones during medial thalamic stimulation. Top traces are cortical surface potentials from the midsuprasylvian gyrus while the bottom ones are the caudate neurone membrane potential. A and B are continous records, while C was obtained from another experiment. The intracellular records were made 1-2 hr after cortical ablation. The EPSP and spike patterns observed are similar to those elicited in cortically intact preparations. (From Purpura and Malliani, 1967; reproduced with permission.)

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50msec FIG. 7. EPSP-IPSP sequences of a ventrally located caudate neurone in response to medial thalamic stimulation. A, B and C are continuous records; the top traces showing cortical surface recordings, while the bottom ones the membrane potential of the caudate cell. In A, the cell exhibits relatively high-frequency spontaneous discharges which are interrupted by small IPSPs. The first thalamic stimulus evokes an EPSP and spike discharges and a succeeding prolonged IPSP (B and C). The spontaneous activity resumes following cessation of the stimulation. (From Purpura and Malliani, 1967; reproduced with permission.)

a direct involvement of a thalamo-cortico-striatal curcuit was ruled out (see Fig. 6), although such a relay circuit may have a facilitatory effect on the thalamo-striatal input (see also Purpura, 1975). Caudate cells with a higher rate of spontaneous discharge often responded with rhythmic EPSP-IPSP sequences on thalamic stimulation (Fig. 7). Similar effects were observed in ventrally located putamen cells. However, in view of the long and variable latencies of the PSPs it was uncertain whether the effects observed were mediated through a monosynaptic pathway. Purpura (1975) suggests, however, that the EPSP-IPSP sequences reflect a process of caudate neuronal synchronization which probably underlies the recruiting-like and spindle-burst EEG activity demonstrated during thalamic stimulation. Thus, the caudate may be involved in many of the transactional processes usually assigned to components of the thalamic nonspecific projection system (Purpura, 1970). The C M - P F input to the striatum does, however, appear to be monosynaptic (based on constant latency responding to variations in stimulus intensity and frequency), and virtually all neurones recorded received converging EPSPs from the cortex and the mesencephalon (Kocsis et al., 1977a) (Fig. 8). Though in this study of thalamic evoked EPSPs, intracellular hyperpolarizing current injections increased, while depolarizing current decreased, the amplitude of the PSPs (suggesting the EPSPs were genuine), no measurements of EPSP reversal potential were achieved. Therefore, as discussed previously regarding the cortico-striatal input, that from the thalamus also appears to be excitatory and the longer latency evoked IPSPs occur as a consequence of activation of intracaudate inhibitory mechanisms. The additional projection from the CM and CL to the putamen has been varified by antidromic stimulation techniques (Rasminsky et al., 1973). These authors suggest that the pathway uses relatively small caliber myelinated or unmyelinated fibers with conduction velocities of 0.1 m/sec to 2-15 m/sec. Additionally, some cells of the VL and VPm (nucleus ventralis postero-medialis) could be antidromically activated by putamen stimulation (see Fig. 4 of Rasminsky et al., 1973), though lack of anatomical support suggested that they might be merely thalamic projecting neurones with collaterals passing through the putamen. Little is known concerning the identity of the neurotransmitters in the thalamo-striate pathway. Neurochemical experiments, based on ChAT measurements following discrete lesions, suggest a cholinergic pathway linking the C M - P F complex to the head of the striatum which takes a course through the STN (Simke and Saelens, 1977; Wagner et al., 1975). It is uncertain, however, whether this pathway is a striatal efferent or afferent. O n J,P.N. 1 4 4 - B

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FIG. 8. EPSPs induced in cat caudate neurones by stimulation of the cortex (Cx, A-CL CMP (D-FI and SN (G-I). A, D and G show the effect of increasing the stimulus intensity. The amplitude increases but the latency remains constant. B, E and H show constant latency responses elicited by one and three shocks. The latency remains unchanged but the response amplitudes increase with three shocks. C, F and I show monosynaptic EPSP latency histograms. Abscissa: latency in reset: ordinate, number of responses. The 10 msec calibration bar in H pertains to the first two rows except for G. The 2 mV calibration bar pertains to the first two rows. Extracellular controls are superimposed in the first two rows and are below the intracellular responses in the third row. Arrows mark the onset of stimulation and the first two rows are signal averaged {n = 4). (From Kocsis et al., 1977: reproduced with permission.) the other hand, neurotransmitter release studies showed that CM stimulation increased DA release from the caudate, though it was uncertain whether this was mediated directly (McLennan, 1964). Early electrophysiological studies by McLennan and York (1966) suggested that neurones in the caudate could be excited or depressed by VA thalamic stimulation, and these effects parallelled those of ACh administered to the same cells by electrophoresis. Moreover, both VA and ACh evoked responses could be prevented by atropine, and this data was in keeping with the enhanced release of ACh from the caudate surface during VA stimulation (McLennan, 1964). These experiments, however, do not provide conclusive evidence that a VA-caudate pathway is monosynaptic, only that Ach may be a transmitter released on caudate target neurones following activation of the synaptic chain. Further experiments identifying thalamo-striatal neurotransmitters are obviously required.

3.2.3. T h e nigro-striatal projection Though lesions in the SN have long been recognized in the neuropathology of P.D. (see Section 2), considerable controversy has surrounded the existence of a nigro--striatal pathway. For example, earlier retrograde degeneration studies suggested its presence, but subsequent histological staining studies denied the existence, possibly because nigrostriatal axons are fine, poorly myelinated and stain with difficulty (for an account of these studies see Carpenter, 1976a, b; Usunoff et al., 1976). Neurochemical studies from postm o r t e m P.D. brains suggested, however, that the loss of striatal DA, coincident with SN pathology and with loss of DA in the SN, indicated the presence of a DA-ergic nigrostriatal pathway. Such a pathway has since been convincingly demonstrated by fluorescence histochemical procedures, indicating that the nigro-striatal DA pathway originated from the medium size cells of the SNC and the ventral tegmental area (Anden et

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al., 1964; Dahlstrom and Fuxe, 1964; Hokfelt and Ungerstedt, 1969; Ungerstedt, 1971a;

Lindvall and Bjorklund, 1974). This pathway seems particularly well developed in the fetal mammalian brain (Nobin and Bjorklund, 1973; Golden, 1972; Tennyson et al., 1973). The nigro-striatal projection has indeed been confirmed with a number of anatomical techniques including retrograde degeneration following nonspecific lesioning or 6-OHDA lesions, as well as in axonal transport studies (Carpenter et al., 1976; Carpenter and Peter, 1972; Moore et al., 1971; Nauta et al., 1974; Sotelo and Riche, 1974; Hattori et al., 1973; Hedreen and Chalmers, 1972; Faull and Carmen, 1968; Schwab et al., 1977). However, other studies suggest that the nigro-striatal DA projection arises only from the pyramidal shaped cells in the ventral most layer of the SNC (Fallon et al., 1978) and that some cells of the SNR (mainly within the ventromedial region of the caudal SNR) also project to the striatum (Usunoff et al., 1976; Royce, 1978b; Vander Maelen et al., 1978b; Faull and Mehler 1978). Indeed, Mettler (1970) reported that the nigro-striatal projection arises mainly from cells in the SNR. Nigro-striatal fibers ascend in the vicinity of the MFB, run along the border of the SN to the prerubral area; proceed for a short distance through the lateral hypothalamus, enter the medial part of the internal capsule and run in a dorso-rostral direction to reach the caudate and putamen. A small number of fibers cross the peduncular part of the internal capsule and then traverse the entopeduncular nucleus and the globus pallidus to terminate mainly in the putamen (Usunoff et al., 1976). The nigro-striatal projections are topographically arranged; thus, in monkeys lesions in the caudal two thirds of the nigra produce degeneration in the putamen and in parts of the body and tail of the caudate. Lateral and caudal SN project predominantly to dorsal putamen whereas medial portions project to ventral putamen. The rostral third of the nigra appears to relate principally to the head of the caudate (Carpenter and Peter 1972; Carpenter, 1976a, b). Cells in the vicinity of the SN also project to the striatum. Thus, e.g., cells in the ventral tegmental area of Tsi (Nauta et al., 1974; Ungerstedt, 1971a), mesencephalic reticular formation (Robertson and Travers, 1975) and retrorubral area (Vander Maelen et al., 1978b; Preston et al., 1978) send sparse projections to the ipsilateral striatum. For the DA-ergic projection at least, nigro-striatal fibers appear to be diffusely scattered in the striatum, but some form well circumscribed islands, revealed by fluorescence histochemistry (Olson et al., 1972). Perhaps these islands represent discrete topographical projections. This latter study also revealed the direct nature of the DA pathway, since fibers could be traced throughout their entire length from the SNC to terminal regions in the ipsilateral striatum. Electron microscopic observations show that nigro-striatal fibers end on dendritic spines and on the cell bodies of spiny neurones and on the dendrites of "spidery" striatal neurones (Kemp, 1968; Fox et al., 1971b). In keeping with the DA-ergic nature of the NSP, neurotoxic (6-OHDA) or electrolytic lesions of the SN produce degeneration of the pathway, loss of striatal DA terminals and reduce striatal DA concentration and that of its synthetic enzymes (Hedreen and Chalmers, 1972; Bedard and Larochelle, 1973; Poirier and Sourkes, 1965; Faull and Laverty, 1969; Hokfelt and Ungerstedt, 1969; Sotelo et al., 1973; Ungerstedt, 1971b; Moore et al., 1971 ; Anden et al., 1966b; Gumulka et al., 1970; Bedard et al., 1969). Moreover, electrical stimulation of the SN increases DA-release from the ipsilateral striatum (Portig and Vogt, 1969; Arbuthnott et al., 1970; Arbuthnott et al., 1971; Nieoullon et al., 1977a). Not all nigro-striatal fibers are DA-ergic, however. This problem raises certain difficulties in electrophysiological studies to confirm the identity of the NSP (see Section 3.2.3.1). Orthograde amino-acid transport studies suggest that some 20~o of nigro-striatal fibers are non-DA (Hedreen, 1971, 1978; Fibiger et al., 1972), while retrograde H R P studies further suggest a population of nigro-striatal neurones which do not stain for TOH, and are thus presumed not to contain DA (Ljungdahl et al., 1975). The non-DA pathway, moreover, appears to take a different course from the DA-ergic one, on route to the striatum (Hedreen, 1978). The cells of origin of this pathway are uncertain, though a

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projection arises in the SNR (Faull and Mehler, 1978). Non-DA nigro-striatal fibers may also be collaterals of the nigro--thalamic projection originating in the SNR (see Section 6.2). 3.2.3.1, Electrophysiological studies Though there is now good evidence, both anatomical and neurochemical, for a direct nigro--striatal DA-ergic projection, the electrophysiological and pharmacological confirmation of its identity is still a subject of debate (e.g. see recent commentaries by Feltz, 1978; Siggins, 1978; Dray, 1979). Electrophysiological studies involving extracellular recording from single caudate neurones show that most cells sampled are depressed; some are facilitated and others undergo complex changes in firing rate, involving reverberating depression and facilitation, on stimulation of the ipsilateral SN (Albe-Fessard et al., 1967; Feltz and Mackenzie, 1969; Feltz and Albe-Fessard, 1972; Connor, 1970; York, 1970; McLennan and York, 1967; Liles, 1974; Zarzecki et al., 1976; Gonzales-Vegas, 1974; Richardson et al., 1977; Frigyesi and Purpura, 1967; Davies and Tongroach, 1978) (Fig. 9). In these studies, evoked inhibition was more readily seen when spontaneous neuronal activity was high or when the characteristically low spontaneous firing was elevated by the electrophoresis of

C

Rec nCoud 200 S t S. Nigro

5bin

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0

!

50

!

!

100

150

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200ms

FIG. 9. The duality of the effectsof nigral stimulation on two differenttypes of caudate neurones in cat. The activity of the larger cell shown in the spike records (A) was depressed and this was followedby a delayedfacilitationshown clearlyin the PSTH (C) summing 200 stimuli. In B (on a faster time scale) a smaller amplitude spike was driven by nigral stimulation. (From Feltz and Albe-Fessard, 1972; reproduced with permission.)

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excitant amino-acids. Many cells, especially if quiescent, are also excited by SN stimulation, the excitation often preceding a period of inhibition. Interestingly, excitatory responses may be suppressed by barbiturate anesthesia (Feltz and Albe-Fessard, 1972). Responsive neurones were considered to be distributed mainly in the medial portions of the head of the caudate (cat) (Frigyesi and Purpura, 1967; Feltz and Albe-Fessard, 1972). Additionally, SN evoked activity of caudate cells was considered to be mediated by a direct nigro-striatal pathway. Thus, evoked responses could still be elicited after chronic destruction of cortico-spinal, cortico-bulbar, medial lemniscal and brachium conjunctival pathways (Frigyesi and Purpura, 1967). Moreover, both orthodromic and antidromic conduction measurements suggest a slowly conducting (~0.9 m/sec) monosynaptic connection (Frigyesi and Purpura, 1967; Lites, 1974; Feltz and Albe-Fessard, 1972). It was, however, surprising and disconcerting that few nigro-striatal projecting cells could be antidromically activated during caudate stimulation (e.g. Hull et al., 1970; Kocsis et al., 1977a; Purpura, 1975; Feltz and Mackenzie, 1969; Dray et al., 1976; Albe-Fessard et al., 1975). The reason for this failure might be attributed to the precise topographical distribution of nigro-striatal afferents. Thus, Guyenet and Aghajanian (1978) were able to evoke antidromic discharges in rat SN neurones more consistently by stimulating and recording from more appropriate localities in the caudate and SN respectively; guided by prior HRP studies of the topography of the nigro-striatal projection system. These authors also showed nigro-striatal projections with separate conduction velocities; the DA-ergic pathway (the major projection) was slow (0.58m/sec), while a smaller number of cells had faster conducting axons (2.8 m/see), and were considered to be non-DA ergic projecting also to the thalamus. Intracellular studies also show transient monosynaptic excitation (EPSPs) of caudate neurones preceding prolonged periods of inhibition (late IPSPs) during SN or MFB stimulation (Buchwald et al., 1973; Fuller et al,, 1975; Hull et al., 1970; Kitai et al., 1976c; Kocsis and Kitai, 1977; Kitai et al., 1975; Bernardi et al., 1978). Moreover, intracellular HRP injections reveal that the monosynaptic EPSP evoked by SN stimulation occurs on the medium size, spiny caudate neurones (Kitai et al., 1976c) and that these cells receive converging EPSPs from other brain regions--e.g, cortex and thalamus (Buchwald et al., 1973; Kocsis et al., 1977a). Nigral-evoked EPSPs in the cat appear to exhibit two components: a slow component (C2) representing a conduction velocity of about 1 m/see, similar to that reported for nigro-striatal fibers by others (see above); and a faster component (C1) representing a conduction velocity of 8.2 m/see, not reported in previous intracellular studies (Kitai and Kocsis, 1978; Kocsis and Kitai, 1977; but see also Guyenet and Aghajanian, 1978, for rat data). It may of course be that anesthesia masked such effects in previous studies (cf. Feltz and Albe-Fessard, 1972). The complex EPSPs are illustrated in Fig. 10. The C1 type response appears to be specific t o SN stimulation, as it was rarely observed during cortical or thalamic stimulation. Moreover, intracellular current injections suggest that the C1 component was a genuine EPSP a n d furthermore was not mediated by the antidromic activation of axon-collaterals of striato-nigral fibers (Fig. 11). Evoked action potentials usually arise only from the larger amplitude C2 component. The synaptic organization underlying the C~ and C2 EPSPs can be distinguished physiologically. Thus, conditioning EPSPs evoked from either cortical or thalami¢ stimulation prior to a test SN stimulation only reduces the C2 EPSP, regardless of the additional presence of any IPSP (Fig. 12). These experiments allow some hypothesis regarding the synaptic localization of the EPSP and IPSP components (Fig. 12). Thus, the C2 afferents may terminate on the bulbous portions of the dendritic spines. These spines may serve to "isolate" electrical events from the dendritic shagt because o f the high" resistance of the spiny stalk (Diamond et al., 1969; Llinas and Hillman, 1969). Such arrangements would allow a high degree of summation from the activation of numerous axospinous synapses (Rail, 1967; Rail et al., 1967). The inhibitory synapses might occur on the main dendritic shaft (Fig. 12) or spine stalk as suggested from anatomical data (Kemp and Powell, 1971c, d). Conditioning EPSPs might thus produce a discharge in

242

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A

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FIG. 10. EPSPs induced in cat caudate neurones from substantia nigra (SN), cortex (CX} or centromedian parafasicular thalamus (CMP) stimulation. A, the two component EPSP (C1 and C2) induced by SN stimulation. B and C show the graded nature and constant latency of the response by variation in the stimulation intensity. E-G show EPSPs in another neurone following SN (EL cortex (F) and CMP (G) stimulation. These were accompanied by spike discharges, (E) and (G). Note the single component EPSP from cortex or CMP stimulation. D and H, EPSP from another neurone during SN stimulation, showing (D) control EPSP and (H) the effect of 1.2 nA of hyperpolarizing current injection, which increases the amplitude of the early C1 EPSP component. The bottom traces in A-C and F are extracellular, and those of E and G are low gain DC. Calibrations are 4 mV (D) for all AC traces, 20 mV (G) for DC traces in E and G; 20 msec calibration (H) for all traces except C and G, which is 10 msec (G). The arrows indicate the onset of the stimulus. (From Kocsis and Kitai, 1977; reproduced with permission.) target neurones, which would subsequently evoke a polysynaptic dendritic inhibition. This arrangement of dendritic inhibition would account for shunting of the axospinous depolarizing current away from the soma (Calvin, 1964; D i a m o n d et al., 1969; Llinas and Hillman, 1969; Llinas and Nicholson, 1969). It is also likely that the C1 E P S P component is unaffected by dendritic inhibition, since it is immune to this current shunting effect, and therefore C1 terminals may end proximal to the inhibitory ones (Fig. 12). With this scheme Kocsis and Kitai (1977) further suggest that the axospinous EPSPs would be ineffective in producing IS spike discharges due to the localization of the inhibitory inputs. On the other hand, C1 E P S P would still be able to elicit axon discharges. Only a few such synapses (located near the soma) would be required to produce a low amplitude, precisely-timed EPSP, but the level of background depolarization produced by the dendritic EPSPs (C2) might be vital to establish conditions favorable for the generation of C1 spike discharges (Kocsis and Kitai, 1977). Although excitation of some caudate neurones during SN stimulation may, on electrophysiological criteria, be defined as antidromically mediated (constant latency spikes, spikes following high-frequency stimulation, collision extinction) due to activation of striato-nigral fibers (Liles, 1974; Feltz and Albe-Fessard, 1972; Frigyesi and Purpura, 1967; Richardson et al., 1977; Davies and Tongroach, 1978), Kocsis and Kitai (1977) suggest that both the Ct and C2 E P S P could emanate from the nigro-striatal pathway. The precise source of the nerve fibers mediating the C~ and C2 EPSPs is, as yet, uncertain, although both components could conceivably originate from nigro-striatal DA-

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ergic fibers with different c o n d u c t i o n velocities. However, it might be m o r e plausible to consider that the fibers of the slower C2 c o m p o n e n t in the cat (Kocsis a n d Kitai, 1977) are a n a l o g o u s to the s l o w - c o n d u c t i n g D A fibers observed in rats ( G u y e n e t a n d Aghajanian, 1978). Thus, the dendritic C2 E P S P s envisaged as establishing a level of backg r o u n d d e p o l a r i z a t i o n m a y use D A as a t r a n s m i t t e r for this purpose. In s u m m a r y therefore, various suggestions have been m a d e c o n c e r n i n g the nigro-striatal i n p u t : e.g., it has b o t h excitatory a n d i n h i b i t o r y fibers (Frigyesi a n d P u r p u r a , 1967), a n d indeed Davies a n d T o n g r o a c h (1978) reported that synaptic i n h i b i t i o n in the c a u d a t e could be evoked in the absence of preceding excitation d e p e n d i n g o n the location of the s t i m u l a t i n g electrode in the SN. This suggests a different a n a t o m i c a l localiza t i o n for the two pathways. O n the other hand, others suggest that the p a t h w a y is principally excitatory a n d that i n h i b i t i o n is p r o d u c e d by secondary o r t h o d r o m i c activ a t i o n of i n h i b i t o r y striatal i n t e r n e u r o n e s (Feltz a n d AlbeFessard, 1972; Fuller et al.,

A

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FIG. 11. The relationship of the Ct EPSP component to the caudate efferent system. A, CI-C2 EPSPs induced from stimulating the medial portion of the substantia nigra (SNm). B, shows the all-or-none constant latency action potential induced from stimulating the lateral portion of the substantia nigra (SN1) while D shows a low gain DC record of the same response. E, shows superimposed records of paired stimulation for collision testing between direct intracellularly induced spikes (conditioning) and synaptically induced SNI induced spikes (test). The upward and downward arrows indicate the onset and offset of the intracellular depolarizing pulse. The first small upward arrow indicates the point at which SN~ stimulation failed to induce an action potential and the second small upward arrow indicates SNt stimulation corresponding to the last action potential. The SNt induced spike is.obliterated when the time between the intracellularly induced spike onset and SN~ stimulation onset is about 9 msec (conduction time and fiber refractoriness of the somatopetal action potentials). C, shows the latency histogram of Ct, EPSPs and antidromic action potentials from SN stimulation. The Ct EPSP occur before the antidromic responses, with no overlap suggesting that Ct is not mediated via an axon collateral of the caudate projection system to the SN. F and G show records of collision experiments between CMP EPSP with spike and SN Ct EPSP. F is the test control SN C~ EPSP with spike discharge followed by longer latency spikes, while G shows stimulation of the SN paired with preceding CMP EPSP with spike discharges. Note that the longer latency spikes have dropped out but the Ct component with spike discharge remains constant. Thus, there is no evidence for collision between SN and CMP spikes. H-J show a similar collision experiment from another caudate neurone. H shows the control CMP EPSP with spikes. I is the test control Ct EPSP, and J shows paired stimulation of H and I with continuous hyperpolarization. Note that the test Ct EPSP remains,though the hyperpolarizing current was of sufficient intensity to block spike discharges. Calibration: 2mV for A, upper trace of H and I, and J; 6mV for B, F and upper traces of G; 20mV for D, E and lower traces of G and H; 20 msec for A, B, F and G; 10 msec D, E and H-J. (From Kocsis and Kitai 1977; reproduced with permission.)

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A

D

+

B

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,

I0 msec

IOOmsec

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FIG. 12. Interactive effects of afferent inputs to caudate neurones. A, shows superimposed traces of double CMP stimulation. Test stimulation begins at the vertical bar of arrow pointing to the right and increases in 10 msec increments. The conditioning CMP EPSP has no apparent IPSP following it, yet the test EPSP is completely absent up to 75 msec and gradually reaches full recovery at 230 msec. B, shows double stimulation of the SN. The control C2 component (dashed lines) has dropped out when the SN was stimulated at a 50 msec interval, but the C~ component is preserved. In C, CMP (control) and SN (test) stimuli were paired. An IPSP can be seen following the conditioning CMP EPSP but an SN induced Ct-C2 EPSP tested during this IPSP shows that only the C2 component drops out while the Ct persists. The control, test control, and test responses are superimposed on this record. D shows a 16 Hz stimulation of the SN where only the C~ EPSP remains since the C2 response is unable to follow this frequency. Each record (A-D) has its own calibrations, The records in C are signal averaged (n = 4). E, shows a diagrammatic representation of the possible synaptic localization of the CI, C2 and inhibitory (1) components on a spiny caudate neurone. The cell is represented as a soma (S) with four initially spine-free dendrites and an axon arising from the conical hillock. Pendunculate d spines (circle with stalk) are placed on distal dendrites. The afferents are labelled as ECt (C~ excitation), EC2 (C2 or C2-1ike excitation) and I (inhibition). (From Kocsis and Kitai, 1977; reproduced with permission.) 1975; K o c s i s a n d Kitai, 1977; R i c h a r d s o n et al., 1977; Hull et al., 1970; H u l l et al., 1973). Finally, e v o k e d i n h i b i t i o n results from the a n t i d r o m i c a c t i v a t i o n of r e c u r r e n t collaterals of the s t r i a t o - n i g r a l n e u r o n e s (those with larger extracellular spikes) which activate i n h i b i t o r y i n t e r n e u r o n e s (Feltz a n d D e C h a m p l a i n , 1972; R i c h a r d s o n et al., 1977). F o r m a n y years the view has been held t h a t m o s t striatal n e u r o n e s are intrinsic, a n d that spiny striatal n e u r o n e s represent a large p r o p o r t i o n of the n e u r o n a l p o o l (see Section 3.1). C a u d a t o - f u g a l fibers essentially p r o j e c t e d f r o m the " g i a n t " a s p i n y n e u r o n e s (e.g., F o x et al., 1971b, 1972; K e m p a n d Powell, 1971b). Recent studies of r e t r o g r a d e H R P t r a n s p o r t following injections into the S N suggest, however, that a larger p r o p o r t i o n of c a u d a t e n e u r o n e s are o u t p u t neurones. These are generally m e d i u m sized a n d n o t " g i a n t " n e u r o n e s (e.g. G r o f o v a , 1975; S o m o g y i a n d Smith, 1979; see also Section 6.3.1). M o r e over, m o s t n e u r o n e s s h o w i n g m o n o s y n a p t i c E P S P s from S N s t i m u l a t i o n were identified (following i n t r a c e l l u l a r H R P injections) as being m e d i u m sized spiny n e u r o n e s with relatively l o n g a x o n s (Kocsis et al., 1977a; K o c s i s a n d Kitai, 1977), suggesting that these might i n d e e d be c a u d a t o - f u g a l . It thus seems possible t h a t a large p r o p o r t i o n o f n i g r o striatal target cells are in fact striatal o u t p u t cells. A l t h o u g h this p o s s i b i l i t y was e x a m i n e d directly by e l e c t r o p h y s i o l o g i c a l m e t h o d s ( K i t a i et al., 1975), m o n o s y n a p t i c P S P were n o t seen in c a u d a t e - n i g r a p r o j e c t i n g n e u r o n e s a c t i v a t e d a n t i d r o m i c a l l y by s t i m u l a t i o n of the SN. Thus, this s t u d y c o n c l u d e d t h a t c a u d a t e n e u r o n e s which project to the S N are n o t directly influenced b y nigral afferents; i.e., there is no direct r e c i p r o c a l r e l a t i o n s h i p b e t w e e n nigral p r o j e c t i n g c a u d a t e n e u r o n e s a n d c a u d a t e p r o j e c t i n g nigral neurones. O t h e r studies a p p e a r to c o n c u r with this view, in that only few c a u d a t e n e u r o n e s (3%)

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receiving monosynaptic PSPs from the SN could also be antidromically activated by SN stimulation (Kocsis et al., 1977a; Fuller et ai., 1975). Indeed, nigro-striatal DA neurones have been suggested to make excitatory contact with striatal output cells which project to the globus pallidus (Bishop et al., 1978; Richardson et al., 1977). In fact, reciprocal connections may be more common than hitherto shown. Thus, a s discussed earlier, stimulation and recording from sites with closed topographical relationships might be revealing in any reexamination of this relationship. 3.2.3.2. Pharmacological studies Though the electrophysiological studies indicate the complex nature of synaptic relationships in the striatum, they provide little insight into the possible neurotransmitters involved. Dopamine is, of course, a major candidate in the nigro-striatal pathway. Most studies involving the microelectrophoresis of DA onto striatal neurones during extracellular recording of neuronal activity conclude that the predominant effect is depression of activity. This is most clearly seen when caudate neurones are spontaneously firing or when firing is evoked by the concomitant administration of an excitant amino-acid such as glutamate or DLH (Herz and Zieglgansberger, 1968; Bloom et al., 1965; McLennan and York, 1967; Siggins et al., 1974; Spehlmann and Stahl, 1974; Spehlmann, 1975; Stone, 1976; York, 1967; Feltz and de Champlain, 1972a; Yarbrough, 1975; Zarzecki et al., 1976; Davies and Tongroach, 1978). While these studies also report a smaller proportion of cells may be excited by DA, others show that DA excites a more significant number of striatal neurones (Spencer and Havlicek, 1974; Bevan et al., 1975; Norcross and Spehlman, 1978a, b). In particular, the majority of DA-sensitive cells in the putamen appear to be excited (York, 1970, 1972a), though these findings were not entirely confirmed by subsequent investigation (Ben-Ari and Kelly, 1976). Anesthesia (particularly barbiturate) is known to influence the responsiveness of neurones to neurotransmitters, though this alone is unlikely to account for the predominance of inhibitory responses to DA. Indeed, these electrophoretic studies were made under a variety of anesthetic conditions as well as in unanesthetized preparations (e.g., see Connor, 1975; Siggins, 1978). It is notable though, that fewer excitatory responses to DA were found in Spencer and Havlicek's study when barbiturate anesthesia was used. On the other hand, it is possible that striatal neurones, like those in other brain areas, possess both excitatory and inhibitory DA-receptors (Krnjevic, 1974). Inhibitory receptors may be preferentially or predominantly activated by extrinsic DA administration under the conditions of electrophoretic experimentation. It may also be that striatal neurones are heterogeneous in their responsiveness to DA, some being depressed while others are excited. It is difficult to speculate further on these possibilities, since in most experiments the physiological or chemical identity of striatal cells studied was not confirmed. However, from these studies the prevailing view has emerged that DA has an inhibitory neurotransmitter function in the striatum. This view is corroborated by neurochemical studies (see Section 3.4). More direct evidence for the identity of DA as the neurotransmitter in the nigrostriatal pathway should arise by comparing its actions with effects of stimulating the pathway on the same striatal neurones. A significant relationship of this kind for synaptic and DA evoked inhibition was reported by McLennan and York (1967), Connor (1970) and Gonzales-Vegas (1974), but these studies also showed that nigral stimulation and DA administration could produce excitatory effects. However, since these actions were not always seen on the same neurones, a correlation of excitatory effects was not obvious. Zarzecki, et al. (1976) suggested, however, that no good correlation exists between nigral stimulation and the effects of DA in the striatum. Few intracellular studies have compared the actions of DA with synaptic activation of striatal nourones. Kitai et al. (1976c), however, have shown that brief (2-100 msec) electrophoretic pulses of DA (10-450 nA) only produced depolarization in some 30~o of caudate neurones which responded with monosynaptic EPSPs during SN stimulation.

246

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G

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FIG. 13. Effects of substantia nigra stimulation and electrophoretic dopamine on cat caudate neurones. A, shows an action potential evoked by SN stimulation. The two top traces are high-gain AC and low-gain DC records respectively. The bottom two traces are the respective extracellular records. B, shows that the administration of dopamine (DA) with a brief pulse (40 nA for 10 msec) produced membrane depolarization. Successive doses of DA show enhanced effects (C is 2nd dose) and D (high gain AC record) and E (low gain DC record) show the 4th dose. Note the action potentials generated by the fourth dose (D and E). F-H show the effects of electrophoretic Na ÷ on this neurone. F is the 1st administration, G, the second and H the fourth.

No depolarization or action potentials are produced. The bottom traces in D, E and H are the extracellular control records. Calibrations: 5mV for high-gain AC records in A-D and F-H; 20 mV for low-gain DC records in A and E; 30 msec for A-H. I, shows the superimposed records of DA-induced depolarizationand spike potentials from another caudate neurone.(From Kitai et al., 1976; reproduced with permission.) Hyperpolarization by DA, expected from the findings of extracellular studies, was never seen. Repeated administrations of DA moreover produced depolarizing responses sufficient to generate action potentials (Fig. 13). Such findings therefore do not readily support the view that repeated DA administration may produce desensitization of excitatory receptors and thus account for the predominance of inhibitory effects observed in extracellular studies where more prolonged administrations of DA (for several seconds) were employed. Siggins (1978), however, argues forcibly that technical artifacts may account for the depolarization observed during brief pulse administration of DA. While such factors may indeed complicate the interpretation of intracellular studies with extracellular drug administration they do not readily explain DA depolarization. For example, recent studies by Bernardi e t al. (1978) suggest that even when DA is administered for prolonged periods, slow depolarization of caudate neurones occurs. A significant feature of this response was the accompanying cessation of background neuronal discharges which related to the rise time of the depolarizations (Fig. 14). Of course, such a response would be observed as inhibition during extracellular studies of neuronal firing. Though membrane resistance was not routinely measured, no changes were reported in most cells tested (six out of seven). In contrast to Kitai e t al. (1976c), Bernardi e t al. (1978) reported that brief pulses of DA (up to 300 msec) were ineffective, and no initial increase in firing was observed, although a firing-rate increase followed some seconds after the end of the DA expulsion (Fig. 14). No convincing explanation for the differences in these findings has been proposed. However, it may be possible that postsynaptic membrane depolarization is accompanied by a reduction of presynaptic excitatory transmitter release, e.g., ACh or glutamate, or that the electrotonic spread of somatic depolarizing current may be sufficient to shunt tonic dendritic EPSPs. It would seem necessary, therefore, to make a more comprehensive comparison of the effects of brief and prolonged DA administrations on quiescent as well as tonically-active neurones, and at the same time provide additional data on the effects of DA on membrane conductance properties.

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Pharmacological manipulations of the nigro-striatal DA-ergic system has also provided a variety of perplexing data. DA-ergic agonists such as amphetamine (which releases DA from terminals) and apomorphine (a direct receptor stimulant) also inhibit striatal neurones, as do other DA-receptor stimulants (Spencer and Havlicek, 1974; Stone, 1976; Woodruff et al., 1976; Zarzecki et al., 1976; Feltz and DeChamplain, 1972a). Also, neuroleptic drugs (e.g. chlorpromazine, haloperidol and flupenthixol), which antagonize the biochemical and behavioral effects of DA-ergic agents in the striatum, block the inhibitory effects of DA when administered microelectrophoretically (York, 1970, 1972a; Norcross and Spehlman, 1978a; Siggins et al., 1974; Siggins et al., 1976; Ben-Ari and Kelly, 1976) (Fig. 15). Also, depression of striatal neurones by DA and by SN stimulation may be antagonized by the catatonic drugs, papaverine and bulbocapnine (Gonzales-Vegas, 1974), by 0t-methydopamine (Connor, 1970) and by ~t- or fl-adrenergic receptor blockers (McLennan and York, 1967; York, 1970). Unfortunately, the selectivity of these agents was rarely determined. Indeed, it would appear that these drugs-neuroleptics in particular--lack sufficient specificity to allow meaninful interpretation of electrophysiological data (e.g. Ben-Ari and Kelly, 1976; Dray et al., 1976b; Feltz 1971a; Davies and Tongroach, 1978) (Fig. 15). On the other hand, others have found that acute or chronic administration of neuroleptics neither produce changes in nigro-striatal evoked inhibition nor changes in the sensitivity of striatal neurones to DA (Zarzecki et al., 1977; Ben-Ari and Kelly, 1976; Bioulac et al., 1978). Alternative approaches have also produced equivocal results. Thus, e.g., stimulation of the SN still evokes excitation or inhibition in the striatum after destruction of striatal DA-ergic terminals with 6-OHDA or following DA depletion by combined pretreatment with reserpine and the synthesis inhibitor ~t-methylparatyrosine (Feltz and de Champlain, A

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FIG. 14. Intracellular recordings from two different striatal neurones (A and D) monosynaptically activated by MFB stimulation (C and E) (three superimposed traces for each record). A, shows the depolarizing action of DA following a prolonged ejection (90 hA). This was accompanied by a decrease of the spontaneous neuronal activity. A similar administration of Na + had no effect. B, shows that the onset of the DA effect was not accompanied by an increase i n firing rate for several hundred milliseconds. D, shows the effect of DA on another caudate neurone. Note, as in A, the prolonged duration of the depolarization produced by DA. (From Bernardi et al., 1978; reproduced with permission.)

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FIG. 15. The effectsof ~t-flupenthixolon dopamine(DA), 5-hydroxytryptamine(5HT) and (GABA) responses of a rat neostriatal neurone A. In B the effect against synaptic inhibition evoked by substantia nigra stimulation is shown. Each PSTH was computed from 80 consecutivestimuli. Flupenthixol reduced the background firing of this neurone and anatagonized the responses to DA and 5HT but not GABA. In B, ~t-flupenthixolreduced the inhibitionbut not the initial brief excitation evoked by nigral stimulation(see b). (From Davies and Tongroach, 1978; reproduced with permission.) 1972b; Feltz et al., 1975). This suggested that neither type of evoked response was likely to be mediated by synaptic DA-release. However, striatal neurones have been suggested to be more sensitive to extrinsic DA following 6-OHDA lesions or chronic haloperidol treatment (Feltz and de Champlain, 1972a; Siggins et al., 1974; Ungerstedt et al., 1975; Yarbrough, 1975), while others report that the sensitivity to DA is decreased after electrolytic lesions of the nigro-striatal pathway (Spehlman, 1975; Norcross and Spehlman, 1978b). The nonspecificity of lesions or indirect trans-synaptic changes which influence receptor sensitivity may account for these differences. It is possible that DA-induced depression and that evoked by SN stimulation might result from an indirect release of GABA in the striatum. Indeed, both picrotoxin and bicuculline were shown to depress nigral-evoked inhibition in the caudate of cats depleted of striatal DA with combined reserpine and ~-MPT pretreatment (Feltz et al., 1975). However, others show that DA-depression is resistant to both picrotoxin and bicuculline (McCarthy et al., 1977; Davies and Tongroach, 1978) and that SN evoked inhibition is also resistant to both bicuculline and locally administered tetanus toxin (Davies and Tongroach, 1979) (Fig. 16). Pharmacological studies of DA excitation have not been much more revealing. Thus, DA excitation in the striatum may be antagonized by a variety of neuroleptics and with ~t- and fl-adrenergic receptor blockers (York, 1970, 1972a; Norcross and Spehlman, 1978a). Also, DA and SN evoked depolarization of caudate neurones (but not excitation produced by cortical or thalamic stimulation) was blocked by neuroleptics (Kitai et al., 1976c; Spehlman and Norcross, 1978), though no rigorous controls for antagonist specificity were applied. Conversely, neither electrophoretic nor systemic ct-flupenthixol influenced SN evoked excitation (Davies and Tongroach, 1978), and blockade of caudate excitation by haloperidol in earlier studies was considered unspecific (Feltz, 1971a). In general, pharmacological studies to identify DA as the neurotransmitter in the nigro-striatal pathway have been disappointing. Certainly, the specificity of DA antagonists is poor, but this does not necessarily mean that an action at DA receptors does not contribute to their neurochemical or clinical efficacy (see Section 3.4). However, the convincing identification of DA as the nigro-striatal transmitter in electrophysiological terms requires the judicious use of more selective antagonists. Moreover, if the nigro-striatal pathway comprises both facilitatory and inhibitory fibers (both DA-ergic and

MAMMALIAN BASAL GANGLIA

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non-DA-ergic), there is yet insufficient evidence to say which of these uses DA as neurotransmitter (but see Section 3.2.3.1). Also, before any conclusions can be reached regarding the action of DA in the striatum, other indirect actions such as those on presynaptic terminals or those mediated via interneurones need to be critically evaluated. Since the role of DA on striatal neuronal activity appears difficult to evaluate with extracellular recording methods, further intracellular studies of DA-induced changes in m e m b r a n e properties need to be made. These should be compared with the effects of discrete stimulation of the truly DA-ergic nigro--striatal fibers.

3.2.4. Brainstem-striatal projections 3.2.4.1. Reticular formation Both anterograde degeneration studies (Lynch et al., 1973; N a u t a and Kuypers, 1958) and retrograde transport of H R P (Robertson and Travers, 1975) suggest diffuse projections to the striatum from the reticular formation (pontine and caudal mesencephalic regions). This projection appears to be minor but can be distinguished from the nigrostriatal fibers on the basis of the latter's finer-caliber fibers (Robertson and Travers, 1975). RF-striatal fibers appear to project bilaterally, but terminations are densest ipsilaterally in the ventrolateral segment of the striatum. Neither the function nor the neurotransmitter in these pathways is known, though stimulation of the mesencephalon or rostral pons evokes slow potentials and multiple cell activity in the head of the caudate nucleus (Robertson et al., 1973). This projection, however, has been considered to be part of the diffuse ascending reticular activating system (Lynch et al., 1973; see also Section 3.2.2.1).

250

A. DRAY

3.2.4.2. R a p h e - s t r i a t a l projection Raphe-striatal projections have been established by a number of techniques. Thus, retrograde or anterograde fiber-tracing experiments suggest a prominent projection mainly from the DRN with a minimal projection from the MRN (Miller et al., 1975; Azmitia and Segal, 1978; Bobillier et al., 1976; Conrad et al., 1974; Jacobs et al., 1978; Royce, 1978b; Pasquier et al., 1977). The DRN projection could not be confirmed by Pierce et al. (1976), possibly due to more caudal placement of labelled tracer in the DRN. However, the raphe-striatal pathway takes a course along the ventro-lateral aspect of the MFB, sends extensive axon collaterals to the SN (Van der Kooy and Hattori, 1979) and ends diffusely in the striatum with densest innervation to caudal parts of the caudate nucleus. The DRN projection appears to be mainly unilateral, though fibers from both DRN and MRN may cross to the contralateral side in the supraoptic commisure, supramammilary commissure, or in the decussation of the brachium conjunctivum (Bjorklund et al., 1973; Bobillier et al., 1976; Conrad et al., 1974; Jacobs et al., 1978; Moore et al., 1978). Observations from fluorescence histochemistry suggest that this pathway may be serotoninergic (Dahlstrom and Fuxe, 1964; Ungerstedt, 1971a). Indeed, the striatum contains significant amounts of serotonin and mechanisms for its synthesis and degredation (Palkovits et al., 1974; Bogdanski et al., 1957; Broch and Marsden, 1972). Additionally, neurochemical procedures following lesions of the raphe show significant reductions of striatal serotonin content, serotonin uptake, and loss of serotonin fluorescence (Moore and Halaris, 1975; Halaris et al., 1976; Bourgoin et al., 1977; Kuhar et al., 1972; Marsden and Guldberg, 1973; Jacobs et al., 1977; Costall et al., 1975; Lorens et al., 1976). In particular, discrete electrolytic or neurotoxic lesions confirm that the major serotoninergic contribution to the striatum arises from the DRN (Dray et al., 1978; Lorens and Guldberg, 1974; Geyer et al., 1976; Jacobs et al., 1974; Moore and Halaris, 1975; Jacobs et al., 1978). However, it is possible that not all DRN projections are serotoninergic, since some neurones remain after 5,7DHT pretreatment (Jacobs et al., 1978). Finally, stimulation of the raphe produces an increase in serotonin release from the striatum (Holman and Vogt, 1972). Electrophysiological experiments involving extracellular recording from striatal neurones show that DRN stimulation produces long-lasting inhibition of firing in the majority of responsive cells (Olpe and Koella, 1977a; Davies and Tongroach, 1978; Miller et al., 1975), though a few cells were facilitated. On the other hand, MRN stimulation produced few effects (Olpe and Koella, 1977a), supporting the differential nature of the raphe-striatal input suggested by anatomical and neurochemical studies. Though both Miller et al. (1975) and Olpe and KoeUa (1977a) report extremely short latency responses of striatal cells upon raphe stimulation, Davies and Tongroach (1978) suggested that raphe-striatal fibers were slowly conducting (0.3-0.7 m/sec), compatible with conduction velocities from other serotoninergic raphe-fungal projections (e.g. Wang and Aghajanian, 1977). Though the constant latency of evoked responses indicates the possible monosynaptic nature of the raphe-striatal projection, no intracellular studies are available to confirm this, or the nature of PSP evoked in striatal neurones (but see below). However, the serotoninergic nature of the DRN projection appears probable, since 5HT has predominantly inhibitory actions on striatal neurones (Herz and Zieglgansberger, 1968), and both its effects and raphe-evoked synaptic inhibitions were antagonized by the 5HT-receptor blocker methysergide (Olpe and Koella, 1977a; Davies and Tongroach, 1978) in amounts which had little effect on inhibition by DA or GABA (Fig. 17). Moreover, it was considered that raphe-evoked inhibition was unlikely to result from direct or indirect release of GABA, since the responses to DRN stimulation were resistant to both bicucuiline and to locally administered tetanus toxin (Davies and Tongroach, 1978, 1979). Though it is not certain what type of striatal neurones receive raphe projections, the fact that many neurones inhibited by DRN stimulation received convergent inputs from the ipsilateral SN (Davies and Tongroach, 1978) suggest that they may be medium

MAMMALIAN BASAL GANGLIA

251

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FIG. 17. Effectsof methysergideon the responses of a rat neostriatal neurone to dopamine (DA), 5-hydroxytryptamine(5-HT) and GABA. The lower record B shows PSTHs of the responses of this neurone to 80 consecutivestimuli of the dorsal raphe nucleus. A shows that methysergide caused a reduction of 5HT responses with little effecton those of GABA or DA. The lower record shows that raphe-induced inhibition was also reduced by methysergide(MS). (From Davies and T0ngroach 1978; reproduced with permission.) sized spiny neurones (Kocsis et al., 1977a). However, as noted in the discussion of the nature of nigro-striatal projection, extracellular observations alone may be misleading. Thus, intracellular studies with transmitter electrophoresis are yet required to verify the raphe-striatal input. Preliminary intracellular studies suggest, however, that DRN stimulation evokes monosynaptic EPSPs and E P S P - I P S P sequences in striatal neurones (Van der Maelen et al., 1979). 3.2.4.3. Amygdala-striatal projections H R P and fiber degeneration studies suggest a sparse innervation from the magnocellular portion of the basal amygdaloid nucleus to the ipsilateral caudate, putamen and globus pallidus (Williams, 1953; Nauta, 1961; Royce, 1978b). The existence of this projection appears to be substantiated by electrophysiological studies showing short latencyevoked responses in caudate following amygdaloid stimulation (Gloor, 1955; Adey, 1959; Russell et al., 1968) and that some caudate neurones respond with short latency following basolateral amygdaloid stimulation (Dafny et al., 1975). Though intracellular studies would be necessary to verify the monosynaptic nature of this projection, the evidence at present suggests that connections of the amygdala provide a pathway through which the limbic system may influence somatic motor activities. 3.2.4.4. Nucleus-accumbens-striatal

projection

On the basis of its location, cytoarchitecture, development and connections, the nucleus accumbens has been considered to be primarily related to either the striatum or the limbic system. In fact it both receives afferents from and sends efferents to "extrapyramidal" and "limbic" structures (Cowan et al., 1965; DeFrance and Yoshihara, 1975; Ito et al., 1974; Nauta et al., 1978; Lauer, 1945; Powell and Leman, 1976; Raisman et al., 1966; Swanson and Cowan, 1975; Hassler, 1978). Functionally, this nucleus has been linked with visceral responses (Gurdjian, 1928; Lorens et al., 1970), olfaction (Johnston, 1923), milk ejection (Woods et al., 1969), alerting in the limbic system (Heath, 1972) and somatosensory activity (Pijnenburg et al., 1973; Kelly et al., 1975; Pijnenburg et al., 1975). Thus, the accumbens has been considered to serve as a "bridge" between limbic and motor systems. Indeed, fiber connections with several basal gangliar structures have been described and will be considered in the appropriate sections (see Sections 4.2.3 and 6.3.6).

252

A. DRAY

Orthograde transport studies of labelled amino-acids suggest projections from the medial portion of the accumbens to the medial part of the head and anterior body of the caudate (Conrad and Pfaff, 1976; Lauer, 1945; Powell and Leman, 1976). Degeneration studies also suggest projections from the caudate to the accumbens, but these may have been due to concomitant damage to the septum (Powell and Leman, 1976; Knook, 1966). No electrophysiological or neuropharmacological verification of accumbens-caudate projections is presently available. 3.2.4.5. Locus-coeruleus-striatal projection Low levels of NA (0.1/ag/g) have been found in the striatum (Farley and Hornykiewicz, 1977) and this appears to be localized to nerve terminals in this region (Lindvall and Bjorklund, 1974). It is suggested that these terminals may arise from a pathway having its source in the NA-cell bodies of the locus coeruleus (Dehlstrom and Fuxe, 1964). Indeed, orthograde axoplasmic flow studies show that labelled amino-acids and 3H-DOPA are transported to the caudate following injection into the locus coeruleus (Jones et al., 1977). This pathway is sparse and projects mainly unilaterally. No electrophysiological confirmation for this projection is currently available. 3.3. STRIATAL EFFERENT SYSTEMS The major and most important efferent pathways of the striatum project ipsilaterally and form the strio-pallidai and strio-nigral projections (see Section 6.3). These pathways were considered to arise from only 5°0 of the large striatal neurones with unmyelinated axons (Kemp and Powell, 1971b; Rafois and Fox, 1975). More recent studies suggest that perhaps 30-50°/o of striatal neurones are output cells (Leontovich, 1954; Bunney and Aghajanian, 1976; Kanazawa et al., 1976; Grofova, 1975; Somogyi and Smith, 1979) and that a significant proportion are the spiny medium sized neurones with fine-caliber axons. In fact, the striatum has been likened to a dome superimposed on the globus pallidus and which sends its fibers into a core, the centrally placed globus pallidus (Szabo, 1962). It should be mentioned, however, that sparse caudate-caudate transcallosal connections have been described (Mensah and Deadwyler, 1974). Their significance is uncertain (but see Section 6.4.1). 3.4. NEUROPHARMACOLOGYAND MICROPHYSIOLOGY OF TRANSMITTERS IN THE STRIATUM

The concentrations of various neurotransmitter candidates in basal ganglia are summarized in Tables 1-4. Perhaps the most intensive investigations of basal gangliar neurotransmitters have been focused on those in the striatum and the SN. Consequently, the attention of this section will be principally directed to these areas (see Section 6.4 for SN discussion), not with the intention of summarizing the diverse pharmacological literature, but to discuss relevant pharmacological and physiological data which provide insight into the mechanisms of transmitter interactions with membrane components and the resulting changes in neuronal excitability. The striatal DA-receptor has received extensive attention with reference to the action of DA-stimulant drugs, neuroleptic agents and the identification of the nigro-striatal transmitter (Section 3.2.3). Dopamine and other DA-ergic agonists such as apomorphine or ADTN (Elkhawad et al., 1975; Woodruff, 1978; Miller et al., 1974; Munday et al., 1974; Ungerstedt, 1971b) produce an increase in striatal cyclic 3151-adenosine monophosphate (c-AMP) by stimulating the activity of membrane adenylate cyclase; a process which can be blocked by antipsychotic drugs (Kebabian et al., 1972; Miller and Iversen, 1974; Walker and Walker, 1973) and by venoms which uncouple the receptor from the enzyme (Kebabian, 1978). The possibility was thus raised that striatal DA-receptors could be functionally linked to membrane cyclase and that c-AMP formation would mediate DA responses (see, e.g.,

MAMMALIAN BASAL GANGLIA

253

Mcllwain, 1977; Phillis, 1977). Support for this hypothesis has been obtained from electrophysiological studies (Siggins et al., 1974, 1976; Woodruff et al., 1976), in which a close correlation was observed between the depressant effects of DA, apomorphine and c-AMP on the firing of single striatal neurones. Moreover, inhibitors of phosphodiesterase (the catabolic enzyme for c-AMP) potentiated DA responses and those of c-AMP when administered by electrophoresis or systemically. Antagonist neuroleptics also blocked the effects of DA, but rarely those of c-AMP. However, control agents were seldom used in these studies to determine the specificity of the interactions observed (Siggins et al., 1974, 1976). On the other hand, behavioral studies support the relationship between DA and cyclic nucleotide mediated effects. For example, in rats with unilateral nigro-striatal lesions, contraversive rotation produced by L-DOPA or apomorphine was increased by the administration of phosphodiesterase inhibitors (Fuxe and Ungerstedt, 1974). Indeed, direct administration of cyclic nucleotides by intrastriatal injection produced contralateral turning similar to that of DA-receptor activation (Satoh et al., 1976). On the other hand, unilateral intrastriatal injections of kainic acid (see also Section 7.4.1), which produced a complete failure of DA to stimulate adenylate cyclase, also caused chronic ipsilateral rotation which was potentiated by apomorphine (presumably due to activation of contralateral striatal DA-receptors). Haloperidol reversed the apomorphine activity into contralateral rotation, suggesting that DA-ergic activity on the lesioned side was now predominating (DiChiara et al., 1977). If the explanation for these behavioral effects is correct it is difficult to envisage how activation of adenylate cyclase could mediate the response. Additional problems are presented since glial cells also possess an adenylate cyclase which may be stimulated by DA and blocked by haloperidol (Schubert et al., 1976; Henn et al., 1977). The functional consequences of this is unclear. Although cyclase-linked DA-receptors may mediate some of the actions of synaptically-released DA, they seem unlikely to account for all of the effects of DA. Apart from being considered as a likely synaptic transmitter, striatal DA has been suggested to be a modulator of carbohydrate metabolism through a DA-dependent, neuroleptic sensitive, adenylate cyclase mechanism (Anchors and Garcia-Rill, 1977; Garcia-Rill and Anchors, 1978; Heller and Hoffman, 1975). Indeed, apomorphine increases glucose utilization in the striatum, globus pallidus, STN and in SN by a neuroleptic sensitive process (Brown and Wolfson, 1978). In addition, changes in cyclase-linked activity may be involved in the mechanism of DA-receptor supersensitivity which occurs after denervation of the nigro-striatal pathway. During this phenomenon there appears to be a Ca 2 ÷dependent increase in a low molecular weight protein associated with the enzyme (Lucchelli et al., 1978). Other experiments do indeed suggest a multiplicity of DA-receptor sites (Fig. 18). Receptor binding studies indicate that post-synaptic DA-receptors may exist in two configurations:one that binds DA-agonists most effectively, e.g. 3H-DA or 3H-apomorphine; and another which binds with antagonists more effectively, e.g. 3H-neuroleptics (Creese et al., 1976; Creese and Snyder, 1978; Seeman et al., 1975; Seeman et al., 1976a; Burt et al., 1975). Additionally, it appears that DA-receptors are present on both presynaptic and postsynaptic membranes. Thus, unilateral 6-OHDA lesions of the nigrostriatal pathway reduce aH-apomorphine binding in the SN and in the striatum, suggesting the presence of DA-receptors on SN neurones and on striatal terminals or axons (Nagy et al., 1978). On the other hand striatal, but not SN, binding of 3H-neuroleptics was increased, suggesting that neuroleptics were bound to intact but otherwise altered postsynaptic membranes. The increased binding may be related to increased striatal receptor sensitivity or an increased number of DA receptors which have been reported to occur in binding studies or implied from behavior studies after similar lesions of the NSP (Muller and Seeman, 1977; Burt et al., 1977; Ungerstedt, 1971b). The unchanged neuroleptic binding in the SN may reflect the intact cyclase-linked DA-receptors on striatonigral or pallido-nigral terminals which are unaffected by 6-OHDA (see Section 6.4.1) (Fig. 18). Kainic acid lesions of the striatum produce almost total loss of DA-stimulated adenyJ.P,~. 144

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late cyclase activity (see Section 7.4.1). This suggests that the cyclase-linked DA-receptors are predominantly located on postsynaptic membranes of non-DA-ergic neurones (McGeer et al., 1976; Schwarcz and Coyle, 1977). Moreover, kainic acid lesions also significantly reduce neuroleptic binding (Fields et al., 1978), suggesting that neuroleptics may bind preferentially to a postsynaptic adenylate-cyclase linked DA-receptor. However, residual binding may also occur on striatal afferents (cf. Govoni et al., 1978). Indeed, Schwarcz et al., (1978) show that afferents from the cerebral cortex possess DA-receptors. Thus, cortical ablation produced a 35~o loss of 3H-neuroleptic binding in the striatum, with a similar loss of basal cyclase activity, but no change in DA-stimulated cyclase activity. However, combined striatal and cortical lesions reduced binding by 70~o. Since most pharmacological effects and the clinical efficacy of neuroleptics correlate best with their potency in binding assays (Creese et al., 1976; Creese and Snyder, 1978; Seeman et al,, 1976b), it was suggested that the DA receptors on cortical afferents may be other major sites of action for these drugs (Schwarcz et al., 1978). Finally, pharmacologically-distinct DA-receptors have been indicated from behavioral studies in addition to the electrophysiological studies mentioned in Section 3.2.3.2. Thus, activation of different DA-ergic receptors produces opposite behavioral effects as measured by compulsive head turning in cats (see e.g., Cools and Janssen, 1976; Cools and Van Rossum, 1976). Excitation-mediating DA effects and inhibition-mediating effects have different anatomical localizations and exhibit a differential pharmacological profile with respect to antagonist drugs. Although the pharmacological and neurochemical evidence suggests that there are several potential sites in the striatum where DA may act, an important question concerns the nature of the striatal target neurones affected by synaptically-released DA. lmmunohistochemical studies suggest that DA terminals make contact with cholinergic neurones and also with noncholinergic neurones which may contain GABA (Hattori et al., 1976; McGeer and McGeer, 1975). Moreover, neurochemical assays following lesions indicate that the striatal cholinergic system is intrinsic, though some ACh may derive from axon terminals of the intralaminar thalamic pathway (McGeer et al., 1971; Butcher and Butcher, 1974; Wagner et al., 1975; Hattori and McGeer, 1974; Simke and Saelens, 1977). A proportion of striatal GABA is also in interneurones (McGeer and McGeer, 1975), whose terminals may take up 3H-GABA (Hokfelt et al., 1970). Presumably, the remaining striatal GABA is contained in the striato-nigral and striato-pallidal pathways (see

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Section 6.3.1), since lesions of the thalamus or cortex produce no significant changes in striatal GAD activity (McGeer and McGeer, 1975; Schwarcz et ai., 1978). Pharmacological studies support the concept of DA-ergic interactions with striatal cholinergic and GABA systems. Such experiments clearly establish that DA has an inhibitory influence on striatal cholinergic neurone activity (Agid et al., 1975a; Consolo et al., 1974; Guyenet et al., 1975; McGeer et al., 1974; Sethy and Van Woert, 1974; Stadler et al., 1973; Trabucchi et al., 1974). On the other hand, 6-OHDA lesions of the nigro-striatal pathway produce a marked increase in striatal ACh concentration, a decrease in AChE activity, with little change in ChAT activity (Kim, 1973; Vincent et al., 1978a). Hemitransection between the striatum and SN, however, has been reported to have little effect on striatal ACh concentration or on ChAT activity (McGeer et al., 1973; Kataoka et al., 1974). Indeed, any activation of striatal cholinergic neurones after nigral lesions appears to be transient (Agid et al., 1975b). Lesion experiments suggest, however, that the increased ACh concentration may result from loss of striatal AChE activity and that the DA system is not the only controlling influence over striatal cholinergic activity. Furthermore, the minimal changes in striatal ACh turnover may result from compensatory activation of nigro-striatal DA-neurones which remain intact after lesioning (Agid et al., 1973). It is also important to bear in mind the electrophysiological data discussed in Section 3.2.4.1, suggesting that the nigro-striatal input is at the membrane level, probably facilitatory. Indeed, Butcher et al. (1976) suggest from lesion experiments that the nigrostriatal DA projection has a net excitatory effect on striatal cholinergic interneurones. Thus, in contrast to the pharmacological studies, it seems more difficult with lesion techniques to show clear-cut relationships between the striatal DA and cholinergic systems. However, as a final note, cholinergic systems appear to be involved in the striatal supersensitivity response to DA-agonists following deafferentation of the NSP. Thus, the apomorphine-induced increase in striatal ACh concentration is magnified two to three fold after 6-OHDA lesions or chronic neuroleptic treatment (Consolo et al., 1978). While neurochemical studies suggest that striatal GAD distribution (mainly in ventrocaudal striatum) and that of DA-sensitive cyclase (mainly rostral-striatum) differs (Koslow et al., 1974; Scally et al., 1978; Fonnum et al., 1978; Bockaert et al., 1976; Tassin et al., 1976), specific lesions of the nigro-striatal DA-pathway or striatal DA-terminals increase striatal GAD activity (Saavedra et al., 1978; Vincent et al., 1978a). Other lesion studies of nigro-striatal inputs show no effect on striatal GAD activity or GABA concentration, but an increase in the rate of accumulation of GABA when metabolism is blocked (McGeer and McGeer, 1975; Racagni et al., 1978). Though the effects observed could be mediated transynaptically, they are also suggestive of a possible direct impingement of DA terminals with inhibitory properties on striatal GABA neurones. Indirect pharmacological support for this view is suggested by the fact that haloperidol reduces striatal GABA concentration, possibly as a result of an increased release, due to blockade of inhibitory DA-ergic influences on GABA-releasing neurones (Kim and Hassler, 1975). On the other hand, 6-OHDA lesions of striatal DA terminals have no effect on striatal GAB& GABA-T or GAD (Kim, 1973). Moreover, Mao and Costa (1978) report that GABA metabolism is reduced following acute haloperidol administration, but augmented by chronic pretreatment. Thus, at present a striatal DA/GABA synaptic relationship appears to be indicated, though this needs to be consolidated and clarified by more comprehensive study. Most electrophysiological studies involving the electrophoretic administration of neurotransmitters agree that ACh excites the majority of striatal neurones, though some cells may be depressed, especially if their background discharge is high (Bloom et al., 1965; Herz and Zieglgansberger, 1968; McLennan and York, 1966; Woodruff et al., 1976; Davies and Tongroach, 1978; Zarzecki et al., 1976). The effects of ACh appear to involve interactions with both muscarinic and nicotinic-type receptors; inhibition being mediated predominantly by muscarinic receptors, while excitation being the property of both types of receptor activation. (McLennan and York, 1966; Herz and Zieglgansberger, 1968).

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Interestingly, barbiturate anesthesia reduces the frequency of encountering cells which are excited by ACh (Bloom et al., 1965; Spencer and Havlicek, 1974). Intracellular studies show that ACh produces a slow depolarization and a progressive increase in striatal cell-firing; effects which can be blocked by atropine (Bernardi et al., 1976a). Though in this study membrane resistance was generally unchanged by ACh, the effects produced resemble the slow "muscarinic" responses to ACh observed in cerebral cortical neurones which is accompanied by a decrease in K ÷ conductance (see Krnjevic, 1974). The striatum, as mentioned previously (see Section 3.2.4.2) contains significant quantities of 5HT localized in nerve terminals which derive from midbrain raphe neurones. The distribution of 5HT is similar to that of GAD-activity, and differs from that of endogenous DA (Fonnum et al., 1978; Bockaert et al., 1976; Tassin et al., 1976). Though few studies have been reported, microelectrophoretic administration of 5HT usually depresses striatal cell-firing, though a small number of cells may be excited (Herz and Zieglgansberger, 1968; Davies and Tongroach, 1978). No information is available regarding the effects of 5HT on striatal-neuronal membrane properties. The inhibitory effects of 5HT may, however, be blocked by antagonists such as methysergide (Davies and Tongroach, 1978). The functional role of striatal 5HT is unclear, though its concentration is reduced in neurological disease (see Section 2) and its actions are implicated in behavioral changes. In particular, there appears to be evidence for an interaction between striatal 5HT and DA systems. Thus, behavioral responses to DA-ergic drugs are potentiated following forebrain 5HT depletion, and decreased by raising 5HT levels (Milson and Pycock, 1976; see also Section 7.4.2). Additionally lesions of the raphe (which deplete forebrain 5HT and 5HIAA) increase striatal DA turnover (Giambalvo and Snodgrass, 1978), and if lesions are asymmetrical the resulting contralateral circling behavior can be enhanced by apomorphine and amphetamine (Costall et al., 1976b; but see also Azmitia and Segal, 1978). Although pharmacological evidence suggests that 5HT agonists like DA may serve to inhibit striatal cholinergic neurones (Euvrard et al., 1977; Samanin et al., 1978), lesions of the raphe-striatal serotonin projection result in a decrease in ACh synthesis, which suggests that synapticaily-released 5HT has a net excitatory influence on striatal cholinergic neurones (Butcher et al., 1976). Since the electrophysiological data (see Section 3.2.4.2) suggests a predominantly inhibitory role for the raphe-striatal pathway, the effects of lesions on ACh synthesis would appear to be exerted indirectly. Moreover, biochemical measurements following lesions of the raphe would not be expected to clarify the role of 5HT in the striatum regarding DA-ergic or cholinergic interactions, since the raphe may also modify striatal activity by way of raphe-nigral-striatal pathways. However, conclusions regarding the role of striatal 5HT seem at present to be premature, especially considering the apparently paradoxical findings with respect to striatal DA function based on intracellular measurements in striatal neurones (see Section 3.2.3.2). Striatal neurones are excited by a number of amino-acids, including glutamate and aspartate (e.g., see Bloom et al., 1965; Spencer, 1976). Unlike the excitant effects of ACh, those of glutamate produce a rapid membrane depolarization, while larger doses also increase spike duration and reduce spike amplitude due to inactivation (Bernardi et al., 1976a; Bernardi et al., 1978). As expected, these effects are accompanied by a decrease in membrane resistance (Bernardi et al., 1976a). On the other hand, amino acids such as GABA or glycine invariably depress striatal cell activity (Bloom et al., 1965; Yarbrough, 1975; Davies and Tongroach, 1978), actions which are antagonized respectively by picrotoxin, bicuculline and presumably by strychnine. The significance of striatal glycine is not apparent, as behavioral studies show no abnormalities following intrastriatal administration of strychnine or glycine (McKenzie et al., 1972; Mendez et al., 1976). Intracellular studies show that depression of neuronal firing by GABA is accompanied by membrane hyperpolarization and an increase in membrane conductance, possibly to CI- (Bernardi et al., 1975; Herding et al., 1978). Similar studies with glycine have not

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been reported. Both electrophoretic picrotoxin and bucuculline antagonized the inhibitory effects of GABA in intracellular studies, but were ineffective against synaptically evoked (from cortex or globus pallidus) IPSPs (Bernardi et al., 1976b), possibly due to inadequate spread of the antagonist to synaptic regions on distal dendrites. However, both alkaloids blocked synaptic IPSPs when administered intravenously. While the studies on the effects of various transmitters on striatal neurones give no indication of the chemical type of neurone recorded from, other lines of evidence suggest that they may influence DA-ergic activity in the striatum. For example, ACh stimulated the spontaneous release of DA from the striatum both in vitro and in vivo. This action involved the activation of both nicotinic and muscarinic receptors localized on presynaptic DA-ergic nerve terminals (Bartholini and Stadler, 1975; Giorguieff et al., 1976, 1977b). McGeer et al. (1979) conclude, however, from receptor binding studies, that cholinergic muscarinic receptors occur on striatal neurones or dendrites, whereas nicotinic receptors are present on afferent dopaminergic and cortico-striatal neurones. However, the release of 3H-DA evoked by K ÷ or electrical field stimulation in in vitro slice preparations (Farnebo and Hamberger, 1971; Iversen et al., 1976; Plotsky et al., 1977; Dismukes and Mulder, 1977; Westfall et al., 1976; Starke et al., 1978) is depressed by ACh (Westfall, 1974). GABA and GABA-mimetic drugs also facilitate K+-stimulated 3H-DA release and stimulate the release of 3H-DA newly synthesized from 3H-tyrosine (Starr, 1978; Giorguieff et al., 1978). On the other hand, tetanus toxin reduced K+-stimulated GABA and DA release from striatal slices, but did not affect the release of 5HT. The changes in DA release were considered to be secondary to those of GABA (Collingridge et al., 1979). The effects of GABA appear to be Ca z ÷-dependent, and are abolished by tetrodotoxin and picrotoxin, suggesting that they are mediated through an action on pharmacologicallydefinable GABA receptors which are not located on presynaptic DA-terminals, but possibly on other striatal neurones or afferents. In vivo studies, on the other hand, reveal that GABA reduces spontaneous DA-release by an action which may be prevented by picrotoxin or bicuculline (Bartholini and Stadler, 1977). It seems possible that the effects of GABA on DA-release in these experimental situations may be concentration-dependent, being facilitatory at low concentrations, but depressant at higher ones (e.g., Cheramy et al., 1978a; Giorguieff et al., 1978). Picrotoxin, however, may in itself cause an increase in striatal DA-release and a reduction in ACh release. These effects are abolished by 6-OHDA lesions of striatal DA-ergic terminals (Javoy et al., 1977) and thus suggest an action on such terminals. Glutamate may also modify striatal DA release. Thus, the glutamate-induced increase in 3H-DA release from striatal slices was blocked by GDEE, but was unchanged in the presence of TTX, and unaffected by anticholinergic drugs, suggesting that the effects of glutamate were not mediated through cholinergic neurones and were unlikely to involve the activation of presynaptic DA-receptors (Giorguieff et al., 1977a; Roberts and Sharif, 1978). Though the changes in DA release produced by various neurotransmitters allow certain speculation concerning their sites of action, they may be of little importance in elucidating synaptic interactions which are of physiological significance. For example, apparent inconsistencies in pharmacological studies such as those of GABA/DA interactions may be due to drug actions on nonphysiological receptors or by indirect actions through polysynaptic neuronal circuits or on unidentified afferent terminals. Recent interest in basal ganglia pharmacology has focused also on the actions of opiates and endogenous opioid peptides (enkephalins). Indeed, the striatum contains significant amounts of enkephalin, and an enkephalin containing striato-pallidal fiber system has been described (Cuello and Paxinos, 1978; Hong et a l , 1977; Yang et al.," 1977; Simantov et al., 1977). Moreover, the highest opiate receptor binding occurs in the striatum, and this may be reduced by 6-OHDA lesions of the NSP (35%) or by kainic acid injections into the striatum (70%) (Kuhar et al., 1973; Pert and Snyder, 1973; Snyder, 1975; Pollard et al., 1977; Minneman et al., 1978; Pollard et al., 1978). Thus,

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opiate receptors appear to be localized to DA nerve terminals and also on striatal postsynaptic membranes. Enkephalin release has been demonstrated from striatal and pallidal slices by K ÷ stimulation, and is a Ca2+-dependent process (Henderson et al., 1978; Iversen et al., 1978). Like opiates, the opioid peptides induce an increase in striatal DA turnover by inhibiting DA-release or by increasing the activity of SN neurones of the NSP (Haveman and Kuschinsky, 1978; Kuschinsky and Hornykiewicz, 1972; Iwatsubo and Clouet 1977; Fukui and Takagi, 1972; Pollard et al., 1978; but see Arbilla and Langer, 1978). This effect on DA turnover appears to be stereospecfic, and is blocked by opiate-receptor antagonists such as naloxone. Additionally, kainic acid lesions of the striatum do not abolish the ability of enkephalin to stimulate DA turnover, suggesting that this activity is confined to an action on DA-ergic terminals (Biggio et al., 1978). When opiates or opioid-peptides are administered to striatal neurones by microelectrophoresis, depression is the usual response reported (Zieglgansberger and Fry, 1976; Bradley and Gayton, 1976; Nicoll et al., 1977; Frederickson and Norris, 1976). It is not known whether this effect is produced by DA release or due to activation of opiate receptors on non-DA striatal neurones. Indeed, it would be of interest to know if the effects of enkephalins were abolished by DA-ergic antagonists or if their actions persist after DA-ergic denervation (e.g. see Bradley and Gayton, 1976).

4. The Giobus Pallidus (Yellow Nucleus of Luys) 4.1. MORPHOLOGY This nucleus lies medial to the putamen and is divided by a medial medullary lamina into medial (internal, GPI) and lateral (external, GPE) pallidal segments, in man and some higher apes, the GPI is usually further divided by an accessory medullary lamina into inner and outer portions (Fig. 19) (Mettler, 1968; Carpenter, 1976a, b; Mehler and Nauta, 1974; Nauta and Mehler, 1966). The term entopeduncular nucleus is used in lower species (e.g. cat, rat) to describe the homologue of the GPI of primates (Fox and Schmitz, 1944; Nauta and Mehler, 1961; Fox et al., 1966). Pallidal neurones are of ovoid or polygonal shape (35-50/am diameter) with long, smooth radiating dendrites (up to 900/~m long) (Fox et al., 1974; Fox et al., 1966). The PALLIDOTHALAMIC PROJECTIONS HORIZONTAL

TR&NSVERSE

FASC

LENT

i

FIG. 19. Schematicdrawingsof the origins and intrapallidalcourse of the ansa lenticularisand the lenticular fasciculusin horizontaland transverse planes. Fibers of the ansa lenticularis arise from the more extensiveregions lateral to the accessory medullary lamina, indicated by the dashed lines. Abbreviations: LPS, lateral pallidal segment; MPS, medial pallidal segment; IC, internal capsule; eL, corpus luysi (subthalamic nucleus); SN, substantia nigra; Fx, Fornix. (From Kuo and Carpenter, 1973; reproduced with permission.)

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long dendrites are usually varicose, with few branches and few dendritic spines which occur in patches or singly, and are well isolated from each other (Kemp, 1970; Kemp and Poweil, 1971e; Fox and Rafols, 1976). Morphologically, there appears to be few differences in the large cells in the two pallidal segments. Afferent fibers run longitudinally in the direction of the dendrites and establish numerous axodendritic synaptic "boutons en passage", as well as axosomatic endings. Fox and Rafols (1976) suggest that there must be considerable convergence of branches from different afferent fibers on individual pailidal neurones. There are also relatively few smaller cells with short axons, suggesting that some intrinsic neuronal circuitry exists. Ultrastructurally, the globus pallidus and substantia nigra are strikingly similar (Fox et al., 1974; Kemp, 1970; Kemp and Powell, 1971c; Rinvik and Grofova, 1970; Schwyn and Fox, 1974). However, in the pallidus, cell bodies are relatively far apart and dispersed throughout the nucleus, whereas in the SN cell bodies are mostly concentrated in the region of the SNC. The predominant type of synaptic ending has large (500-700 A) egg-shaped synaptic vesicles (Fox et al., 1974), which form symmetrical synapses and which degenerate following lesions in the striatum (Kemp, 1970; Fox et al., 1975; Kemp and Powell, 1971c). Other nerve endings contain small synaptic vesicles and have been considered to be terminals of subthalamic fibers (Fox et al., 1974; Carpenter and Strominger, 1967; Nauta and Cole, 1974).

4.2. CONNECTIONSOF THE GLOBUS PALLIDUS There are a number of afferent projections to the globus pallidus; the main projections, however, are those from the striatum and the subthalamic nucleus (see Fig. 20).

FIG. 20. Schematic representation of connections of the giobus pallidus. No indication of the respective density of projections is intended. Key: CX, cortex; STR, striatum; AC, nucleus accumbens; thalamic nuclei VL, ventro-lateral; VA, ventro-anterior; DM, dorso-medial; CM-PF, centromedian-parafascicular complex; GPI, internal pallidal segment; GPE, external pallidal segment; SNC, substantia nigra pars compata; SNR, substantia nigra pars reticulata; LH, lateral habenular nucleus; PP, pedunculo pontine nucleus; STN, subthalamic nucleus; CBN, cerebeilar nuclei. Recent electrophysiological studies indicate that the PP is a source of excitatory input to the GPI and GPE (Gonya-Magee and Anderson, 1979.)

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4.2.1. Striato-pallidal projection This forms the most significant afferent pathway of the pallidus and is organized in a topographical manner. Thus, the head of the caudate projects to dorsal and rostral pallidus, whereas the putamen projects to the ventral and caudal parts (Szabo, 1962, 1967, 1970; Voneida, 1960; Nauta and Mehler, 1966; Cowan and Powell, 1966; Carpenter, 1976a, b). Fibers from the putamen have been suggested to project mainly to the external pallidal segment (Cowan and Powell, 1966). Striatal efferents consist of fine caliber, delicately myelinated radial fibers which converge on the pallidus and continue by way of the "comb bundle system" towards the SN (Wilson, 1914; Papez, 1941; Fox and Rafols, 1975; Fox et al., 1975). The radial fibers give off collaterals to both segments of the pallidus. Interestingly, the radial fibers undergo a reduction in caliber (thinning of axis cylinder and reduction of myelin sheath) as they traverse the pallidus. Thus, before entering the pallidus, radial fibers have a mean axis cylinder of 0.68 ~m, whereas fibers of the comb bundle have a mean axis of 0.21/~m (Fox et al., 1975; Fox and Rafols, 1976). The significance of this change is uncertain, though preliminary electrophysiological observations show that repetitive stimulation of these fibers increases their excitability and conduction velocity, suggesting that they may operate as integrative elements which respond in terms of their previous activity (Kocsis et al., 1977b). 4.2.1.1. Electrophysioloyical studies Extracellular studies in monkeys and cats reveal that neurones of the globus pailidus are either slowly firing (1-10 Hz) with large spikes ( > 2 mV) or the majority have high discharge rates (10-100 Hz) with smaller action potentials (Noda et al., 1968). Moreover, cells of the GPI can be distinguished from tho~e of the GPE on the basis of firing patterns. Neurones with frequency discharges separated by periods of quiescence are more often encountered in the GPE while neurones in the GPI show mainly continuous firing patterns (DeLong, 1971, 1972; Ohye et al., 1976). Stimulation of the caudate or putamen (monkey) most commonly produced 10 msec latency inhibitory-excitatory sequences in the dorsal GPE. A smaller number of cells responded by inhibition or excitation, the effect observed often being dependent on background neuronal discharge. Similar effects were observed in the GPI, though there was little convergence of caudate and putamen fibers onto the same pallidal neurones (Ohye et al., 1976). Essentially similar patterns of activity were observed in studies of cat globus pallidus, though the prolonged duration of evoked inhibition was notable (Noda et al., 1968). Though initial studies failed to find evidence of antidromic activation of caudate neurones during entopeduncular stimulation (Hull et al., 1970), these were subsequently shown to occur with long latency, and could also be evoked by ipsilateral SN stimulation (Liles, 1974; Fuller et al., 1975). The early intracellular data of Malliani and Purpura (1967) had already revealed that pallidal-entopeduncular neurones showed EPSP-IPSP sequences (see also Levine et al., 1974a) following repetitive caudate stimulation. However, the most consistent response was a long, but fixed, latency "pure" IPSP, occasionally preceded by a subthreshold EPSP. A monosynaptic, slowly conducting ( 4 1 m s e c -1) caudate-pallidal pathway appeared probable (Purpura, 1975; Liles, 1974; Malliani and Purpura, 1967), and this was confirmed by subsequent intracellular studies (Yoshida et al., 1971, 1972). Moreover, these latter authors reported that no EPSPs preceded caudate evoked IPSPs, suggesting that caudate-pallidal fibers were purely inhibitory. It is possible, however, that the barbiturate anesthesia used in these studies may have depressed evoked excitation. Additional evidence derived from interactions of IPSPs evoked in entopeduncular neurones by caudate and SN stimulation suggests that entopeduncular IPSPs are generated by axon collaterals of caudato-nigral fibers, which are inhibitory in both the entopenduncular nucleus and SN (Yoshida et al., 1972) (Figs 21, 22). However, the possibility of separate caudate and putamen projections to pallidal neurones was not excluded (Yoshida et al., 1972).

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i

I

!

*

'4"

lOOrnsec _10.5rnV

FIG. 21. Interaction between substantia nigral (SN) and caudate-evoked IPSPs in an ENT cell (entopeduncular nucleus = ENT). A-D, show caudate stimulation which evokes an IPSP is followed by SN stimulation at intervals of 75 (A), 160 '(B), 220 (C) and 300msec (D). The amplitude of the caudate IPSP was always slightly greater than that of the SN-evoked IPSP. The SN-evoked IPSP was markedly depressed by a preceding caudate IPSP is the stimulus interval was less than 150 msec. This suggests that both the caudate and SN-evoked IPSPs were generated, at least partly, by activation of the same fibers. E, shows an IPSP evoked by the SN alone. (From Yoshida et al., 1972; reproduced with permission.)

Since neurones of the globus pallidus receive branches of striato--nigral fibers, it is to be expected from Dale's principle, that the neurotransmitter should be the same in both regions. Good evidence exists that the striato-nigral inhibitory transmitter is GABA (see Section 6.3.1.2). Pharmacological and histochemical studies also suggest that GABA is the strio-pallidal inhibitory transmitter (e.g. Ribak et al., 1979). Thus, caudate evoked inhibition of entopeduncular neurones was suppressed by systemically administered GABA antagonists, picrotoxin and bicuculline, but not by the glycine antagonist, strychnine (Obata and Yoshida, 1973). Entopeduncular neurones were also depressed by electrophoretically administered amino acids, but although the effects of GABA and glycine could be selectively antagonized by their respective antagonists administered in a similar way, caudate evoked synaptic inhibition could not. Obata and Yoshida (1973) suggested that insufficient amounts of antagonist reaching remote inhibitory synapses on pallidal dendrites may account for this inconsistency. Clearly, further studies of this kind are required. Furthermore, in view of the EPSPs evoked by caudate stimulation, the possibility of an additional excitatory projection should be considered. Such a projection may in fact also comprise collaterals of the striato-nigral excitatory pathway, which might use a peptide neurotransmitter (see Sections 6.3.1.2 and 6.3.2).

B

,,

t*ll'i"

20msec I 0.SmV

FIG. 22. Potentials evoked in the entopeduncular nucleus (ENT) by substantia nigra (SN) stimulation after chronic ablation of the caudate and putamen (3-7 weeks beforehand), The line drawing in A shows the microelectrode track through the mid-ENT. Marks on the track are 1 mm apart. B, shows potentials evoked by SN stimulation recorded at the positions indicated by the arrows in A. No positive field-potentials could be evoked by SN stimulation indicating that caudato-nigral fibers send inhibitory axon collaterals to the ENT. (From Yoshida et al., 1972; reproduced with permission.)

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4.2.2. Subthalamo-pallidal projection Both silver degeneration and autoradiographic tracing techniques suggest that the subthalamic nucleus gives rise to a considerable projection via the subthalamic fasciculus to all parts of the globus pallidus (Carpenter and Strominger, 1967; Carpenter et al., 1968; Nauta and Cole, 1974; Carpenter, 1976a, b). These fibers appear to be arranged in laminae, orientated parallel to the strio-pallidal border. In the rat the majority of subthalamic neurones appear to send bifurcating projections to both the globus pallidus and substantia nigra (Hattori and Van der Kooy, 1979). Initial extracellular studies suggested that activation of pallidal neurones by subthalamic stimulation was mediated by multisynaptic pathways. The responses consisted of 4-10 msec latency facilitation or inhibition of cell firing (Noda et al., 1968). Moreover, no evidence for antidromic activation of STN neurones could be obtained during GPI stimulation (Ohye et al., 1976). However, Yoshida et al. (1971, 1972) reported that diencephalic stimulation produced monosynaptic IPSPs of short latency in cat entopeduncular neurones; but although the stimulus threshold for the IPSP was low when the STN was stimulated it could not be concluded that this was the origin of the inhibitory fibers. A more recent study, however, appears to confirm that the STN-entopeduncular pathway is directly inhibitory. Thus, the activity of a small number of entopeduncular cells (14~o) classified as projecting neurones (mainly to the lateral habenular nucleus) by antidromic stimulation techniques, was invariably suppressed at short latency following low intensity stimulation of the STN (Larsen and Sutin, 1978). Although the sensitivity of pallidal neurones to microelectrophoretic glycine led Yoshida (1974) to suggest that this amino acid may be the subthalamo-pallidal transmitter, clearly such evidence alone is insufficient. Thus the chemical transmitter in this pathway is unknown and remains to be elucidated. 4.2.3. Other pallidal afferents Sparse projections have been described from the SN which ascend through Forel's field H and terminate in the internal pallidal segment (Ranson and Ranson, 1942; Fox and Schmitz, 1944; Carpenter and McMaster, 1964; Cole et al., 1964). Indeed, only a few pallidal cells show short latency IPSPs following SN stimulation (Yoshida et al., 1971, 1972). Afferents from the red nucleus (Johnson and Clemente, 1959), the nucleus interstitialis (Hassler, 1956) and the medial lemniscus (Mettler, 1945) have been described, as well as fibers from the cerebellum (Mettler, 1968), cerebral cortex (Truex and Carpenter, 1969; Petras, 1972) and from the contralateral pallidum (Lange et al., 1976). On the whole, cortico-pallidal fibers have not been readily observed (see Carpenter, 1976a, b). A number of studies have shown projections from the nucleus accumbens, particularly to the medial and ventromedial parts of the pallidum (Smith, 1930; Williams et al., 1977; Conrad and Pfaff, 1976; Swanson and Cowan, 1975), though this was not entirely confirmed (Powell and Leman, 1976). Moreover, Nauta et al. (1978) suggest that accumbenspallidal projections distribute entirely to the external pallidal segment. The accumbenspallidal projections appears, however, from extracellular electrophysiological studies, to have facilitatory and inhibitory components (Dray and Oakley, 1978). Lesions of the accumbens significantly reduce pallidal GABA concentration and suggest that the inhibitory pathway may use this amino acid as the neurotransmitter (Dray and Oakley, 1978). Additionally, a number of autoradiographic studies have demonstrated a diffuse projection, with moderately dense terminal fields, from the DRN to the globus pallidus and entopeduncular nucleus (Bobillier et al., 1976; Pierce et al., 1976; Moore et al., 1978). Axoplasmic transport in these fibers is abolished by 5,6-DHT pretreatment (Halaris et al., 1976). Since the pallidus has a significant content of 5HT (19.0ng mg -1 protein) (Palkovits et al., 1974), it is tempting to speculate that this may originate from the serotonin cell bodies of the DRN. Obviously, electrophysiological and pharmacological experimentation is required to substantiate the nature of this projection.

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4.3. PALLIDAL EFFERENT SYSTEMS

While the input to the globus pallidus appears to be convergent, pallidal efferents are generally highly divergent and constitute the major efferent systems of the basal ganglia (Nauta and Mehler, 1966; Mehler and Nauta, 1974; Ranson and Ranson, 1939; Glees, 1945; Larsen and Sutin, 1978; Carpenter, 1976a, b; Kim et al., 1976). Cytoarchitecturally, cells of the internal and external pallidal segments are similar, though these portions of the globus pallidus have distinctive projections (Kuo and Carpenter, 1973) arranged into three distinct fiber bundles, the ansa lenticularis, the lenticular fasciculus and the pallidosubthalamic system (Fig. 19) (Grofova and Rinvik, 1974; Grofova, 1970; but see also for rat, Knook, 1965; Severin et al., 1976). Cells of the GPI give rise to the major efferents and there appears to be a topographical relationship between pallidal efferent and afferent projections. 4.3.1. Pallido-subthalamic projection Anterograde axon degeneration studies show that the GPE projects in a topographically organized manner to the subthalamic body. Fibers from the rostral and central GPE project to the rostral two thirds of the STN. Rostral parts of the GPE project to the medial half of the STN, whereas central parts project to the lateral half of STN (Fig. 23) (Nauta and Mehler, 1966; Ranson et al., 1941; Carpenter et al., 1968). A small mediocaudal part of the STN receives no fibers from the GPE, but receives fibers from the GPI (Carpenter et al., 1968). There is also some kadication of somatotopic organization within the STN itself (Mettler and Stern, 1962). In rats, Carter and Fibiger (1978) show pallidal projections to the medial part of the STN. Few electrophysiological studies have been concerned with the pallido-subthalamic pathway, possibly because the STN is small, deep seated in the brain and presents difficulties for stereotoxic localization of recording electrodes. However, extracellular studies in the awake monkey (Ohye et al., 1976) revealed that stimulation of the GPI produced only short latency depression of STN neurones (Fig. 24). These STN neurones were also excited by stimulation of the caudate and putamen; the excitation being followed by a period of inhibition (Fig. 25). Although these data were supportive of possible direct striatal-STN fibers (Johnson, 1961; Niimi et al., 1970), a view not widely held (Kim et al., 1976; Nauta and Mehler, 1969), these responses may also have been generated through polysynaptic circuits involving the globus pallidus (Ohye et al., 1976). However, the earlier intracellular studies of Frigyesi (1968; Frigyesi and Rabin, 1971) in

ROSTRAL

CENTRAL

Subtholomi¢ nucleus

CAUDAL

Fro. 23. Schematic diagram of pallido-subthalamic projections in a horizontal plane.- The topographical organization of efferent fibers from the lateral or external (GP1) and medial or internal (GPm) pallidal segments is evident. In this diagram the subthalamic nucleus appears as a miniature globus pallidus. AC, anterior commissure; III, third ventricle; F, fornix; IC, internal capsule; SN, substantia nigra; LG, lateral geniculate body. (From Carpenter, 1976; reproduced with permission.)

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FIG. 24. Raster dot display showing convergent responses in a subthalamic nucleus (STN) neurone. Stimulation of the globus pallidus (GP} produced a marked arrest of spontaneous activity (extracellular recordings)while stimulation of the anterior or posterior portions of the putamen (Put, p and Put, a) or caudate (Cd. p and Cd. a) induced a short latency spike discharge followed by a period of depression of spontaneous activity. (From Ohye et al., 1976; reproduced with permission.) unanesthetized cats showed that single or repetitive stimulation of the globus pallidus evoked short latency (2-3 msec), monosynaptic EPSPs in STN neurones (Fig. 26). Conversely, pallidal neurones could be driven antidromically by STN stimulation. Pallidal evoked IPSPs often followed monosynaptic spike discharges, occurred with longer latency (15-20 msec) and were prolonged (50-80 msec). During repetitive stimulation these IPSPs fequently exhibited gradual buildup and prolongation. The prolonged IPSPs also rendered STN neurones unresponsive to excitatory influences from sources other than the pallidum. In addition, STN neurones showed short latency EPSPs followed by an IPSP after stimulation of the putamen but not of the ipsilateral caudate (cf. extracellular findings of Ohye e t al., 1976). Neurones in the STN usually show a good deal of spontaneous activity, this being more regular during anesthesia (Tsubokawa and Sutin, 1972). During barbiturate anesthesia, however, pallidal evoked inhibitions in STN neurones were significantly more prolonged than in locally anesthetized animals, and under the former conditions short latency evoked spike discharges were rarely observed (Tsubokawa and Sutin, 1972). Thus, the electrophysiological studies suggest that the pallido-STN pathway is mainly excitatory though the possibility of inhibitory fibers should be considered. Barbiturate anesthesia may in fact preferentially reduce activity in the excitatory pathway. Little is nown about neurotransmitters in the pallido-STN pathway. Neurochemical studies, however, suggest that the pallido-STN pathway may use GABA and thus sup-

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FIG.26. Intracellularlyrecorded responses of a subthalamicnucleus(STN) neurone during globus paltidus {GP)stimulation.A, shows the spontaneous activityof this cell. B, single shock stimulus of the GP elicits a monosynaptic EPSP with a superimposed spike discharge and a slight succeeding IPSP. In C, superimposed traces show 8 Hz GP stimulation of evoked short-latency IPSPs. The superimposed spike discharges exhibit stable latencies, and the GP evoked IPSPs progressively increase in amplitude and shorten in latency during repetitive stimulation. D, during prolonged 8 Hz stimulationthe GP evoked IPSP is of full size and monosynapticactivity is no longer demonstrable. Abbreviations: Cx, motor cortex; STN, subthalamic nucleus; GP, globus pallidus. (From Frigyesiand Rabin 1971; reproduced with permission.) port the suggestion of an additional inhibitory pathway. Thus, lesions of the pallidus produced a unilateral reduction of GAD activity in the STN which followed a general trend expected from the topographical distribution of pallido-STN fibers (Fonnum et ai., 1978). Moreover, cell bodies of the globus pallidus take up aH-GABA, and such cells may give rise to GABA-ergic terminals in the STN as well as the SN (Hattori et al., 1973). Though the STN shows considerable AChE and modest AChT activity (Kobayashi et al., 1975; Olivier et al., 1970), suggesting the possibility of a cholinergic input, excitation of STN neurones by G P stimulation was insensitive to atropine. Thus, it seems unlikely that the pallido-STN excitatory transmitter is ACh (Feger, et al., 1979). As yet we have no insight into the possible nature of the pallido-STN excitatory transmitter nor pharmacological confirmation of pallido-STN projections. The STN also receives sparse afferents from the cerebral cortex (Grofova, 1969; Petras, 1965, 1972) and the MRN (Conrad et al., 1974; Bobillier et al., 1976) and projects to the SNC (Kanazawa et al., 1976). This provides additional circuitry whereby STN activity can be influenced and in turn regulate basal gangliar activity (but see Section 5.3.). 4.3.2. Pallido-thalamic projections In primates, the GPI gives rise to the ansa lenticularis (from the outer GPI) and lenticular fasciculus (from the inner GPI), which follow distinct courses related to the internal capsule, merge in Forel's field H, and then pass rostrally and laterally in the thalamic fasciculus (Kuo and Carpenter, 1973; Carpenter, 1976a, b) (Figs 19,20). The majority of fibers of the thalamic fasciculus terminate in the pars oralis (VLo) and pars medialis (VLm) of the ventrolateral thalamus (VL), and in the pars principalis (VApc) of the ventral anterior thalamic nucleus. Pallido-thalamic fibers are topographically organized such that rostral parts of the GPI project predominantly to VApc, whereas caudal parts project primarily to VLo. Also, dorsal and ventral portions of the GPI project to dorsal and ventral regions of the VApc and VLo. Thus, pallido-thalamic projections are organized in a dorso-ventral and medio-lateral dimensions, but with considerable overlap (Kuo and Carpenter 1973; Carpenter, 1976a, b). Pallidal projections to the centre median nucleus of the thalamus (CM) are organized in a dorso--ventral dimension with the greatest number of terminals in the rostral and medial portions of the nucleus (Carpenter, 1976a, b).

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In rats, silver degeneration and autoradiographic tracing methods show that pallidothalamic fibers project as two diffuse groups to the reticular thalamic nuclei (VA, ventral anterior; VD, ventral dorsal; VM, ventral medial) and to the medial parts of the VE (ventral external) (Severin et al., 1976). More specifically, the entopeduncular nucleus (GPI of primates) projects to VM; the ventral-lateral/ventral-anterior thalamic complex (VALv) and to the parafascicular nucleus (Carter and Fibiger, 1978; Herkenham, 1979; Clavier, et al., 1976). Thus, the pallido-thalamic fibers in the rat appear to project to similar thalamic target areas as those in primates, since it is considered that the VM in the rat is homologous to parts of the VA and VL of primates and the VM, VL of cats (Rinvik, 1975; Faull and Carman, 1968; Carpenter et al., 1976; Clavier et al., 1976; Faull and Mehler, 1976; Carter and Fibiger, 1978). It should be noted that there are fibers projecting to the thalamic nuclei from both the SN and the cerebellum. Thus, the SN projects to VL and VA (VM in rats) and to the C M - P F nuclear complex (Carpenter and Peter, 1972; Carpenter and Strominger, 1967; Cole et al., 1964; Afifi and Kaelber, 1965; Faull and Carmen, 1968; Clavier et al., 1976; Carter and Fibiger, 1978; Kultas-Ilinsky et al., 1978), while cerebello-thalamic fibers (from deep cerebellar nuclei) distribute, via the brachium conjunctivum, throughout the VL and .VA and to other thalamic nuclei (Mehler and Nauta, 1974; Carrea and Mettler, 1954; Kievit and Kuypers, 1972; Cohen et al., 1958; Kemp and Powell, 1971e; Rinvik and Grofova, 1974). However, in the VL, pallidal projections appear to terminate in the rostral subdivisions, whereas cerebeUar projections end in the caudal portions (Nauta and Mehler, 1966; Hassler, 1966; Carpenter and Strominger, 1967; Kusama et al., 1971; Mehler, 1971; Kuo and Carpenter, 1973; Kim et al., 1976). Macroelectrode recordings in the VL show that stimulation of the entopeduncular nucleus (cats) produced 10012 msec latency slow waves, accompanied by spike discharges with little evidence of inhibition (Dormont and Ohye, 1971). Subsequently, Uno et al. (1978) reported that a positive-negative spike followed by a smooth positivity occurred in the VL-VA complex during entopeduncular stimulation. Moreover, an inhibitory nature of the smooth positive field-potential was indicated by the concomitant suppression of background neuronal discharges (Fig. 27). It appears that the largest inhibitory potential could be recorded in the rostro-medial VL and stimulation of this area produced antidromic potentials in the entopeduncular nucleus (Uno et al., 1978). In Dormont and Ohye's study (1971), entopeduncular stimulation activated few cells in the VL (17-200 under chloralose anesthesia; 4-31 in unanesthetized cats). These responses consisted of either excitation followed by inhibition, inhibition, or prolonged excitation. These authors therefore concluded that entopeduncular influences on the VL were weak, compared to those of the cerebellum. On the other hand, intracellular studies have been more revealing, though not without interpretive problems (see discussions in Purpura, 1975; Bruggencate, 1975a). These studies on the whole have also been concerned with convergence of pallidal inputs and those from the contralateral cerebellar nuclei (dentate, interposition and fastigial) via the brachium conjunctivum onto thalamic neurones. Stimulation of the ansa lenticularis evoked short latency (0.7--0.9 msec) monosynaptic EPSPs in VL neurones (cats, pentobarbitone anesthesia) generally associated with a single spike discharge (Fig. 28). VL neurones also responded with short latency EPSPs to stimulation of the contralateral brachium conjunctivum; these PSP were frequently succeeded by prolonged IPSPs (Purpura et al., 1965; Desiraju and Purpura, 1969). In fact, some 20~o of VL neurones studied by Desiraju and Purpura received converging monosynaptic excitatory inputs from both pallidum and cerebellum. These cells were considered to be thalam(r-cortical relay neurones. Additionally, many VL neurones received convergent, but different, inputs from these structures, possibly as a result of polysynaptic activity. For example, Fig. 28 shows that ansa lenticularis stimulation evokes a longer latency (4-5 msec) IPSP, whereas BC stimulation produced a similar latency EPSP. A third population of neurones showed long latency (10030msec) EPSP-IPSP sequences following ansal stimulation, but were rarely activated by BC stimulation.

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lOins FIG. 27. Inhibition of thalamic neurones produced by stimulation of the entopeduncular nucleus (ENT). Records A-D, E-G and H were obtained from three different cells. A, C, and D show IPSPs evoked in a thalamic neurone by ENT stimulation recorded at different sweep speeds. B is the extracellular field potential for A. E, shows superimposed ENT-evoked IPSP while in F the PSP are reversed by passage of hyperpotarizing current. G, shows the corresponding extracellular record with a small positive field-potential indicated by the oblique arrow. H, shows suppression and a rebound facilitation of the spontaneous discharges of a thalamic cell by ENT stimulation. In I, the superimposed traces of E and F are marked with an arrow showing the diverging point of the two curves and indicate the moment of onset of the IPSP. J, frequency distribution histogram of IPSP latencies for 88 thalamic neurones studied. Calibration: 100 msec for A-C and 30 msec for E-G. D and H are DC recordings. Voltage scales: 5 mV for A-H. (From Uno et al., 1978; reproduced with permission.)

These findings were broadly confirmed by Frigyesi and Macheck (1970) and Frigyesi and Rabin (1971), showing that entopeduncular stimulation elicited EPSP and spike discharges in neurones of the VL, VA-VL complex and in the medial thalamus (CM-PF complex). These neurones were monosynaptically activated by BC stimulation, but not from the internal capsule or cerebral peduncular axons (Frigyesi and Machek, 1970). Longer latency EPSP-IPSP sequences, considered to be polysynaptically mediated, were also observed (Frigyesi and Machek, 1970; Frigyesi and Rabin, 1971). Through neurones in the CM-PF complex, like those in the VL, also showed short latency (2-3 msec) EPSPs during entopeduncular stimulation, they had additional distinctive properties. Thus, periodically, depolarizing potentials in CM-PF neurones summated, producing EPSP of 80-200 msec duration associated with repetitive (up to 300 Hz) spike discharges. On the other hand, background activity of VL or DLT (dorsolateral thalamus) neurones seldom exceeded 150 Hz (Frigyesi and Rabin, 1971). Though neurones in the DLT were also activated by entopeduncular stimulation, their long latency EPSP-IPSP sequences suggested activation through polysynaptic pathways (Nauta and Mehler, 1966; Frigyesi and Rabin, 1971). These neurones, however, apparently establish complex synaptic relationships with each other and with other (VL, DL and DM) thalamic neurones. Recent studies by Larsen and Sutin (1978) show that entopeduncular neurones may be antidromically activated from a number of sites, but most (27~) were activated by stimulation of the VA, 13~o from the CM, and very few by VL. These studies also suggest that some entopeduncular inputs to the VA and CM may originate from the same neurones. Thus, in summary so far, a small portion of VL-relay neurones receive monosynaptic excitatory inputs from the pallidum and cerebellum. A population of VL neurones show reciprocal synaptic actions due to interneuronal activation during stimulation of lenticulofugal and cerebello-fugal projections (Frigyesi and Macheck, 1970, 1971;

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FIG. 28. lntracellular recording of convergent monosynaptic excitation of a VL thalamic neurone by ansa lenticularis (A, C and D) and brachium conjunctivum (B) stimulation. Note the minimum latency differences of EPSPs in B and C. Ansa lenticularis evoked EPSP is shown in isolation in D. E and F, show records obtained from a different VL neurone following ansal (E) and brachium conjunctivum (F) stimulation. Only the brachium evoked EPSP is succeeded by a prolonged IPSP, the early phase of which exhibits low amplitud.e oscillations. G and H, are examples of convergent but reciprocal synaptic effects observed in a VL neurone following ansa lenticularis (G) and brachium conjunctivum (H) stimulation. Responses in each case were elicited at two levels of membrane polarization. G, upper record during spontaneous discharges, lower record during a phase of increased membrane polarization in which spontaneous discharges were eliminated. In each instance ansa lenticularis stimulation evokes a 4-6 msec IPSP. H, lower record of the pair obtained during a spontaneous long-duration IPSP. Brachium conjunctivum stimulation elicits a 4 ~ msec latency EPSP and spike discharge. The EPSP is revealed in isolation during the spontaneous IPSP. I-L, show examples of similar long-latency EPSP-IPSP sequences elicited in a VL neurone by repetitive stimulation in the nucleus entopeduncularis region (I and J are continuous records) and stimulation of the medial thalamus (K and L, continuous recordings). The upper records on these traces were obtained from the motor cortex. Note the prominent long-latency surface negative recruiting response evoked by medial thalamic stimulation. (From Desiraju and Purpura, 1969; reproduced with permission.) Frigyesi a n d Rabin, 1971). Finally, a larger a n d m o r e dispersed p o p u l a t i o n of V A - V L a n d m e d i a l nuclei i n t e r n e u r o n e s exhibit similar p a t t e r n s of P S P s following repetitive e n t o p e d u n c u l a r - a n s a lenticularis s t i m u l a t i o n ( P u r p u r a , 1975). G e n e r a l l y , therefore, the p r i m a r y s y n a p t i c event p r o d u c e d in p a l l i d o - - t h a l a m i c n e u r o n e s is the E P S P . O n the o t h e r hand, o t h e r s ( U n o a n d Yoshida, 1975; U n o et al., 1978) r e p o r t that low-intensity stimulation o f the e n t o p e d u n c u l a r (cat, p e n t o b a r b i t o n e anesthesia) p r o d u c e s p r e d o m i n a n t l y short latency (1-6 msec) m o n o s y n a p t i c I P S P s in V L - V A neurones, and suggest a c o n d u c tion velocity of 5-11 m/sec for this p a t h w a y . These e v o k e d I P S P s were usually followed by a small d e p o l a r i z a t i o n . A n e x a m i n a t i o n of the stimulus intensities used revealed that I P S P s were e v o k e d with lowest t h r e s h o l d when the s t i m u l a t i n g e l e c t r o d e was within the e n t o p e d u n c u l a r o r in the internal capsule j u s t d o r s o - m e d i a l to the e n t o p e d u n c u l a r nucleus (Fig. 29). These p o i n t s a p p a r e n t l y c o i n c i d e with the course of the e n t o p e d u n c u l a r p a l l i d a l fibers (Grofova, 1970). T h o u g h in p r e v i o u s studies (cf. Frigyesi a n d M a c h e k , 1970) close a t t e n t i o n was p a i d to stimulus spread, U n o et al. (1978) r e p o r t that e v o k e d E P S P s c o u l d be f o u n d in V L relay cells only with s t r o n g e r s t i m u l a t i o n of the e n t o p e d u n c u l a r nucleus or the internal capsule, suggesting the possibility that such effects were in fact p r o d u c e d b y the s p r e a d of the s t i m u l a t i n g c u r r e n t to a d j a c e n t structures. O n the

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other hand, it is also possible that the use of barbiturate anesthesia by Uno et al., may have depressed excitatory synaptic transmission in the entopeduncular-thalamic pathway. Additionally, Uno et al. (1978) suggest that few of the neurones studied (59/0) received converging inputs from the entopeduncular and the cerebellum. Thus, cells affected by entopeduncular stimulation were located rostrally in the rostral VA and in the medial portion of the rostral VL-VA complex, whereas thalamic relay cells were found in the dorso-lateral portions of the VL-VA and in the caudal VL. Neurones receiving converging inputs were located in the border between these groups. These data thus suggest that the major influences of the pallidal and cerebellar projections on VL-VA neurones occur through intrathalamic polysynaptic pathways. There is little dispute concerning the monosynaptic excitatory nature of the thalamic projections from the contralateral cerebellar nuclei (Angaut et al., 1968; Cond6 and Angaut, 1970; Angaut and Bowsher, 1970; Uno et al., 1970; Desiraju and Purpura, 1969; Frigyesi and Machek, 1971). Also, there is agreement concerning a monosynaptic pallido-thalamic projection (see above). However, the discrepancies concerning the excitatory or inhibitory properties of the pallido-thalamic input need resolving, especially regarding the possible complications of stimulus spread and the effects of general anesthesia on synaptic activity. For the present it may be more constructive to assume that this pathway like others in basal ganglia has mixed excitatory and inhibitory properties. It is important to mention at this point that the VL and the C M - P F complex is topographically and reciprocally connected to primary motor-sensory areas, particularly cortical motor areas four and six, which respectively control limb and axial musculature (Frigyesi and Schwartz, 1972; Kuypers and Brinkman, 1970; Strick, 1970; Woolsey, 1958; Massion and Rispal-Padel, 1972a, b; Catsman-Berrovoets and Kuypers, 1978; Jones and Leavitt, 1974; Marshall and McLennan, 1971). Such feedback circuits inform the motor cortex about modulations of cortical motor outputs performed within the cerebellum and

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FIG. 29. Threshold stimulus intensities for evoking IPSPs in VA-VL neurones from ENT stimulation. A, computer-averaged IPSPs (eight sweeps) evoked in a thalamic neurone by pulses of 0.2 mA applied to six stimulating sites shown in B and C. Traces a-f in A correspond to the stimulation sites in B and C of frontal views of the middle (B) and caudal (C) ENT regions. The transverse section in C was about 2 mm caudal to B. D, shows the distribution of IPSP thresholds in a transverse section in and around the ENT at the frontal level of its middle portion. Thresholds; open circles, <0.2 mA; filled circles, 0.2-0.4mA; crosses > 0.4 mA. Abbreviations: ENT, entopeduncular nucleus; CI, internal capsule; TO, optic tract; R, nucleus reticularis thalami; GP, globus pallidus; Put, putamen. (From Uno et al., 1978; reproduced with permission.) J.P.N, 1 4 / 4 - - D

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basal ganglia respectively (see discussion in Bruggencate, 1975a). Indeed, following experiments involving lesions of the frontal cortex, Garcia-Rill et al. (1979a) recently suggested that the C M P F complex may act as a fulcrum to balance inputs from the cerebral cortex to the caudate nucleus with other outputs from basal ganglia. Thus, excitation of caudate neurones by cortico--striatal inputs might be reinforced by concurrent direct or indirect (via other thalamus nuclei) cortical excitation of the CM-PF complex, which would also excite caudate neurones. Moreover, any increases in the activity of basal gangliar inputs to the thalamus might cancel this excitatory reinforcement, either by direct inhibition of thalamic neurones or by disruption of their firing patterns. On the other hand, a decrease in basal ganglion inputs to the thalamus would enhance the reinforcement by excitatory cortical inputs. Therefore, the C M - P F influence on the caudate would depend on cortical activity, and thus lesions of the C M - P F complex alone should have little net effect on the firing of caudate neurones, which indeed has been reported (Levine et al., 1974b). However, further electrophysioiogical support for this hypothesis appears necessary. Some 60°o of VA-VL neurones projecting to the motor cortex also receive monosynaptic inputs from the cerebellar nuclei (Frigyesi and Machek, 1970). However, VA-VL neuro.nes activated by entopeduncular stimulation appear not to project directly to the cortex (Frigyesi and Machek, 1970), and thus the entopeduncular nucleus must influence cortical activity indirectly. On the other hand, neurones of the C M - P F complex (medial thalamic neurones of Frigyesi and Macheck, 1970) which show monosynaptic EPSPs during entopeduncular stimulation may project directly to the neocortex (Frigyesi and Machek, 1970). Indeed, antidromic studies (Rasminsky et al., 1973: Albe-Fessard et al., 1971) confirm direct projections from medial thalamic neurones to pericruciate cortex. These cells may in fact also send collaterals to subcortical structures, e.g. the putamen. Extensive cortico-thalamic projections, mainly from areas four and six also exist (Peacock and Combs, 1965; Petras, 1965, 1972; Rinvik, 1972; Strick et al., 1972) which innervate neurones in the VL and C M - P F complex. In keeping with these data, short latency excitation in VL and medial thalamic neurones has been shown during cortical stimulation (Frigyesi and Macheck, 1970: Frigyesi and Schwartz, 1972: Uno et al., 1970: Nakamura and Schlag, 1968; Sakata et al., 1966: Rispal-Padel and Massion, 1970). Motor cortex stimulation also induces inhibitory effects in VL and C M - P F neurones, which appear to be mediated indirectly via intrathalamic interneurones (Purpura and Cohen, 1962; Ishida, 1977; Bruggencate, 1975b). Such inhibitions may be blocked by systemically administered strychnine, but not by picrotoxin, suggesting that the interneurones may use glycine as the inhibitory transmitter (Ishida, 1977). The activity of thalamic neurones may also be influenced by sparse projections from the amygdaloid nucleus (Veening 1978), projections from the raphe (Bobillier et al., 1976; Conrad et al., 1974; Pierce et al., 1976), and by a substantial monosynaptic pathway from the SN (see Section 6.2.1). Some nigro-thalamic target neurones, particularly in the VA-VL, may also receive convergent inputs either from the entopeduncular nucleus or the cerebellar nuclei, but these cells rarely project upon the cortex or receive cortical afferents (Frigyesi and Machek, 1970). Indeed, the longer-latency striatal evoked PSPs in thalamic neurones (Frigyesi and Machek, 1970, 1971; Krauthamer and Dalsass, 1978; Frigyesi and Rabin, 1971) may be mediated indirectly via the pallido-thalamic or nigrothalamic pathways. However, Purpura et al. (1967) provide electrophysiological evidence for the possibility of a direct caudate projection to the rostral thalamus (see Fig. 21 in Purpura, 1975). Regarding neurotransmitters in the entopeduncular-thalamic pathway, very little is known. On the basis of electron microscopic observations, three different types of synaptic boutons have been identified in the VL and VA, belonging to the cortical, cerebellar and pallidal afferents (Harding, 1973a, b: Grofova and Rinvik, 1974; Rinvik and Grofova, 1974). Lesions of the entopeduncular nucleus resulted in degeneration of boutons, which established symmetrical synapses with the proximal dendrites and soma of thalamic neurones. These boutons, containing pleomorphic vesicles, have been assumed to be

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inhibitory (Uchizono, 1965). The identity of this putative inhibitory transmitter is unknown, as is that of a possible excitatory transmitter. 4.3.3. Other pallidal projections The GPI gives rist to several sparse projections whose functional significance is not well understood. 4.3.3.1. Pallido-tegmental fibers These fibers descend from Forel's field H and at caudal midbrain levels pass dorsally to terminate in the pedunculopontine nucleus (Nauta and Mehler, 1966; Carpenter and Strominger, 1967; Kim et al., 1976; Carter and Fibiger, 1978). The projection has been confirmed electrophysiologically by antidromic stimulation of projecting fibers, and it was shown that some pallido-pedunculopontine projecting neurones also send projections to the VA and CM nuclei of the thalamus (Larsen and Sutin, 1978). 4.3.3.2. Pallido-habenular fibers These fibers appear to separate from the ansa lenticularis and the lenticular fasciculus near the apex of the globus pallidus (Nauta and Mehler, 1966). By taking multiple and divergent routes, via the stria medullaris, these pallidal fibers terminate in the lateral habenular nucleus (Nauta and Mehler, 1966; Kim et al., 1976; Carter and Fibiger, 1978; Nauta, 1974). The projection has been confirmed by an electrophysiological study (Larsen and Sutin, 1978), which also revealed that pallido-habenular neurones receive an inhibitory input from the STN. Pallido-habenular fibers appear to originate mainly from the entopeduncular nucleus (GPI) (Nagy et al., 1978a). Moreover, lesions of the entopenducular nucleus or G P produces a significant loss of GAD activity (36Yo) in the lateral habenula (Nagy et al., 1978a; Gottesfeld et al., 1977), suggesting that this pathway may utilize GABA as a neurotransmitter. Through the pallido-habenular pathway the striatum has access to limbic circuits. Indeed, the lateral habenula receives projections from septal and preoptic areas, and projects both to preoptic areas, the lateral hypothalamus and the central grey (Herkenham and Nauta, 1977a, b, 1979). 4.3.3.3. Pallido--nigral fibers Pallido-nigral fibers have been suggested and confirmed by several studies (Nauta and Mehler, 1966; Johnson and Clemente, 1959; Kim et al., 1976; Grofova, 1975; see also Section 6.3.2.). Neurochemical studies following pallidal lesions suggest that this pathway uses GABA as a neurotransmitter and thus, like the striato-nigral pathway, is likely to be inhibitory (Hattori et al., 1973; McGeer et al., 1974; Hattori et al., 1975; Ribak et al., 1979).

5. The Subthalamic Nucleus (STN) 5.1. MORPHOLOGY This nucleus is an abundantly vascularized lens-shaped structure lying dorsal to the cerebral peduncles and internal capsule but rostral to the SN. The lenticular fasciculus borders it dorsally, while caudally it is bordered by the zona incerta (Mettler, 1968). Few studies are available describing the cytoarchitecture of the STN (Cajal, 1911; Whittier and Mettler, 1949a; Mettler, 1968; Rafols and Fox, 1975). However, from golgi studies, Rafols and Fox (1975) describe three types of neurones: local interneurones, and two types of principal neurones, radiating and elongated fusiform. Radiating neurones have a few delicate somatic spines, some of which are occasionally bilobed or trilobed and give off five to eight dendritic trunks with long (up to 400/~m) tapering dendrites. These dendrites, however, are much thinner than the robust ones described in the G P or

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SN. Dendritic spines are often found concentrated on dendritic trunks and proximal dendrites. The relatively few elongated fusiform neurones are found both in the dorsal and ventral convexities of the nucleus, as well as in the center. Dendrites (up to 750 #m) emerge from the opposite poles of the smooth-surfaced cell bodies. Local interneurones have small, oval-shaped cell bodies and a few relatively long undulating dendrites with bulbous appendages and beaded axon-like processes.

5.2. SUBTHALAMIC EFFERENT PROJECTIONS

Fiber connections of the STN have been difficult to demonstrate because the nucleus is small, lies close to the internal capsule and multiple fiber systems traverse its immediate vicinity. More recent autoradiographic techniques show that perhaps the major connections are those with the GP forming a unique reciprocal fiber system (Fig. 21) (discussed in Sections 4.2.1. and 4.3.1). Additional projections have been described to the SN (see Section 6.3.5).

5.3. SUBTHALAMICAFFERENT PATHWAYS As mentioned above and discussed in Section 4.3.1 the major afferent pathway to the STN is that from both segments of the GP (Fig. 23). Other afferents exist though their significance is not presently understood. For example there appears to be a significant projection from neurones in the SNC (Cambell et al., 1979).

5.3.1. Cortico-subthalamic projections Though relationships with the cortex have been denied or have been described as sparse (Levin, 1936, 1949; Verhaart and Kennard, 1940; Mettler, 1947a, 1968), well organized projections from the precentral gyrus have been described in primates (Petras, 1969, 1972). These have since been confirmed by a number of studies (Kunzle, 1976; Kunzle and Akert, 1977; Hartmann-von Monakow et al., 1978; Romansky et al., 1979) showing somato-topically organized projections from the precentral motor cortex to the ipsilateral STN with a less intensive projection from the premotor and prefrontal cortices. No electrophysiological studies confirming the direct nature of these projections have been reported.

5.3.2. Raphe-subthalamic projections Orthograde axoplasmic flow of labelled amino acids indicate a sparse projection from the MRN to the STN (Bobillier et al., 1976). Since the STN contains significant amounts of 5HT (ll.2ng/mg protein; Palkovits et al., 1974) it seems reasonable to speculate that it may derive from terminals of raphe projections. No further evidence concerning this seems to be presently available.

5.4. NEUROTRANSM1TTERSIN THE STN

Table 3 shows that the STN contains a number of putative transmitter substances. Their localization has not been systematically explored, though it is evident from previous discussions that some may be contained in afferent terminals and in STN cell bodies (see Sections 4.2.2, 4.3.1, 6.3.5). Recently, however, postsynaptic muscarinic cholinergic excitatory receptors have been identified in rat STN neurones (Feger et al., 1979), though it could not be concluded that these were present as targets for the excitatory transmitter released by striatal or pallidal stimulation.

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6. The Substantia Nigra 6.1. MORPHOLOGY The substantia nigra appears bilaterally as a band of cells between the cerebral peduncle and tegmentum, extending through the length of the midbrain. The neuromelanin pigmentation in this nucleus is found in primates but not in other species (Marsden, 1961). For descriptive purposes the SN has commonly been divided into two distinct regions: the pars or zona compacta (SNC), a cell-rich region, and the pars reticulata (SNR), which as a well organized neuropil but relatively fewer cells. The SNC lies dorsal to the SNR; the latter forming the bulk of the nucleus (Gulley, 1970; Gulley and Smithberg, 1971; Gulley and Wood 1971; Carpenter, 1976a, b; Schwyn and Fox, 1974). Golgi studies reveal that most of the receptive surface of the SN is located on the relatively spine-free dendrites in the SNR (Cajal, 1911; Rinvik and Grofova, 1970; Schwyn and Fox, 1974). Spiny dendrites are, however, common in preparations of SN from young mammals; these appear to be lost on maturation (Schwyn and Fox, 1974). Though descriptions of the SN have been concerned with cell body configuration, the bulk' of the neurones in the SN is made up from the long radiating dendrites. Thus, the neurones of the SNC send apical dendrites into this region, into the ventral tegmental areas, and also long, relatively unbranched dendrites (500-1000 pm) which project downwards into the SNR. Neurones in the SNR, however, distribute their dendrites mainly within this region. Thus, in reality, there appears to be considerable overlapping of cell structures within the two subdivisions of the SN, and indeed it has been suggested that there is no good anatomical basis for considering this nucleus as two distinct regions (Rinvik and Grofova, 1970; Schwyn and Fox, 1974). More recently, a closer study of the dendritic profiles of SN neurones suggests that the nucleus can be considered to be arranged in three layers: a superior layer comprising the SNC; an intermediate layer including the dorsal aspect of the SNR where SNC and SNR dendrites run rostro-caudally and dorsoventrally; and a peripeduncular layer where dendrites from all areas run parallel to the cerebral peduncle (Juraska et al., 1977). Additionally, Faull and Mehler (1978) endorse the subdivision of the SN into SNC and SNR regions and suggest, moreover, that the SNR is divisible on connectional and cytoarchitectonic criteria into subnuclei with discrete afferent projections. Also, neurones (containingDA) of the S N C may be considered to be arranged into two layers with separate morphologies and projections (Fallon et al., 1978). The ventral-most layer consists of pyramidal shaped cells (the most numerous cell type) with varicose dendrites extending into the SNR and axons projecting with mediolateral and anterior-posterior topography to the ipsilateral striatum. The other group of cells are located dorsally in the SNC, have fusiform shapes with dendrites extending medially and laterally within the SNC and send axons to the olfactory tubercle and amygdala. Relatively little attention, either anatomical or physiological, has been given to the pars lateralis of the SN, phylogenetically the oldest part of the SN (Crosby et al., 1962). Though this structure has not been considered separately from the SN (Rinvik and Gofova, 1970; Schwyn and Fox, 1974), it is depicted as a small elliptical mass of neurones lying lateral to the SNC and SNR (Hanaway et al., 1970; Juraska et al., 1977). It forms connections with the SNR through large dendrites arising from large and medium size neurones and has cytological characteristics similar to both areas of the SN. There appears to be considerable variation in cell-body size and shape of SN neurones. In general, three types of neurone have been described: large (45-74/zm) and medium (19-46/am) sized neurones which project to other regions, and smaller neurones (11-26/~m) with small dendritic fields and short axons (Cajal, 1911; GuUey and Wood,. 1971; Schwyn and Fox, 1974; Juraska et al., 1977; Francois, et al., 1979). Medium sized neurones of the SNC give rise to the nigro-striatal projection, while the medium and large neurones of the SNR have axons (sometimes branched) which may project outside the SN and are likely to be the source of the nigro-thalamic and other efferents (Afifi and

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Kaelber, 1965; Faull and Carman, 1968; Carpenter and Peter, 1972; Schwyn and Fox, 1974; Rinvik, 1975; Faull and Mehler, 1978)(but see also sections on nigral efferents). Synaptic contacts in the SN are characterized by "longitudinal axodendritic" arrangements (Schwyn and Fox, 1974). Thus, there are numerous boutons "en passage", allowing a single fiber to make numerous contacts with a single dendritic process. Synaptic boutons are seen mainly on dendritic processes within the SNR, with relatively few on the soma (Rinvik and Grofova, 1970). Synaptic endings comprise those with large vesicles with no dense core (90~o) and may be terminals of striato-nigral fibers; those with small vesicles which may also originate from the striatum and larger endings with sparse pleomorphic vesicles, possibly endings of interneurones. There are also many endings containing dense core vesicles, possibly related to DA-neurone collaterals or raphe projections. Apart from numerous axodendritic and axosomatic contacts, axoaxonic synapses have been described to occur on the axon-hillock or on another synaptic endings within the SN (Grofova and Rinvik, 1970; Rinvik and Grofova, 1970; Kemp and Powell, 1971c; Gulley and Smithberg, 1971; Schwyn and Fox, 1974). 6.2. EFFERENT PROJECTIONS OF THE SUBSTANTIA N1GRA Perhaps the most widely recognized and intensely studied projection of the SN is the nigro-striatal tract. The evidence for its existence and identity of the neurotransmitters involved has been discussed in Section 3.2.3. Studies employing axonal transport techniques have considerably extended the knowledge on other nigral efferents. These are principally a nigro-thalamic, and a nigro-tectal projection with other minor projections to other structures (Fig. 30). Each of the populations of principal nigro-fugal neurones exhibit a different size distribution and localization of the constituent neurones, suggesting a longitudinal subdivision of the SNR into three component subnuclei (Faull and Mehler, 1978) (Fig. 31). Pathways of the SN are summarized in Fig. 30. 6.2.1. The nigro-thalamic projection The nigro-thalamic pathway arises mainly from large non-DA-ergic multipolar neurones of the SNR, ascends into and through Forels field H, and terminates on larger cells within regions of the VA (magnocellular part), and VL (medial part) (VA/VL equivalent to VM of rats) thalamic nuclei (Cole et al., 1964; Faull and Carmen, 1968; Fibiger et al., 1972; Rinvik, 1975; Carpenter et al., 1976; Clavier et al., 1976; Faull and Mehler, 1978; Kultas-Ilinsky et al., 1978; Herkenham, 1979). Additional SN projections have been described to the paralaminar parts of the dorsomedial thalamic nucleus (DMpl) (Carpenter, 1976; Carpenter et al., 1976) which is known to project to the cortical frontal eye fields (Scollo-Lavizzari and Akert, 1963). Clavier et al. (1976) also describe SN projections to the C M - P F complex (rats), though this projection has not received general verification by other investigators (Carpenter et al., 1976; Kultas-llinsky et al., 1978; but see also electrophysiological evidence below). Nigro-thalamic neurones appear to form a longitudinal column of cells within lateral and central regions of the SNR (Faull and Mehler, 1978) (Fig. 31). 6.2.1.1. Electrophysioloffy and transmitter identity of niffro-thalamic projection Several electrophysiological studies have substantiated the presence of nigro-thalamic projections. Thus, extracellular studies show that stimulation of the SN may produce a number of complex changes in thalamic neurone firing, consisting of short and long latency excitations, as well as short and long latency inhibition (Bendrups and McKenzie, 1974; Albe-Fessard et al., 1975; Deniau et al., 1978d). Short latency (6 msec) inhibition was, however, the predominant response in cat VL neurones (Deniau et al., 1978d). The short latency excitation, which exhibited monosynaptic features, disappeared following pericruciate decortication, while short and long latency inhibition as well as long latency excitation remained. This suggested that short latency excitations resulted from activation of cortico-thalamic fibers while the long latency excitation was considered to be

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FIG. 30. Schematic representation of connections of the substantia nigra, Key: STR, striatum: CX, cortex (these connections are disputed); GP, globus pallidus; AC, nucleus accumbens; SNC, pars compacta; SNR, pars reticulata; thalamic nuclei, VL ventrolateral, VA, ventroanterior, DM, dorsomedial; CM-PF, centromedian parafascicular complex; AM, amygdala: STN, subthalamic nucleus; R, raphe (dorsal and medial); CBN, cerebellar nuclei; SC, superior colliculus; RF, reticular formation: LC, locus coeruleus (this projection has been inferred). There is electrophysiological evidence for an input from the anterior olfactory nucleus to the SNC (Tulloch and Arbuthnott 1979). Also, Herkenham and Nauta (1979) have described projections from the medial and lateral habenular nuclei of the rat to the SNC. Various efferent projections from the substantia nigra are mainly derived from different neurones, but a double-labelling method recently confirms that part of the neurones which distribute fibers to the SC also distribute collaterals to the thalamus (Bentivoglio et al., 1979).

b FIG. 31. Summary diagram showing the principal location of the nigral cells projecting to the tectum, thalamus and striatum Within the rostral (a) and the caudal (b) portions of the substantia nigra: Cells within the pars compacta region (dorsal aspect of figures) project to the striatum, while the pars reticulata portion is divisible into three complementary longitudinal subnuclei projecting respectively to the tectum, thalamus and striatum. (From Faull and Mehler, 1978; reproduced with permission.)

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FIG. 32. Left: identification of a relay neurone in the VL nucleus of the thalamus along the cerebeUothalamocorticalpathway. This cell exhibits an antidromic spike after precruciate cortical (CX) stimulation, characterized by stability of latency (top left) and collision with spontaneous activity (middle left). The same neurone was activated monosynapticallyby brachium conjunctivum (BC) stimulation (bottom left). Right: dot display illustrating inhibition of BC evoked responses during stimulation of the ipsilateral substantia nigra (SN). The first three sequences show control response to SN stimulation (note different time bases) and BC stimulation (single shock). Followingsequencesshow inhibition of BC monosynapticdischarges by conditioning SN stimulation. Values on the left side of each sequence represent delay of nigral conditioning and BC testing shock, respectively. Note that the onset of inhibition started with an increase in latency of the test response (sequence 10-12). (From Deniau et al., 1978d; reproduced with permission.} polysynaptically mediated (Albe-Fessard et al., 1975; Deniau et al., 1978d). Significantly thalamic relay neurones identified by monosynaptic cerebeUar activation and antidromic activation following cortical stimulation (32~o of recorded VL cells) were only inhibited with short latency following SN stimulation. This inhibition was, however, strong enough to interupt the operation of the cerebello-thalamic relays (Albe-Fessard et al., 1975; Deniau et al., 1978d) (Fig. 32). Brief latency inhibition following SN stimulation also occurred in the C M - P F complex and ventral median nuclei of the thalamus (Bendrups and McKenzie, 1974; Deniau et al., 1978d). Antidromic stimulation studies confirm the monosyrmptic nature of the nigrothalamic (VM, VL) projections and show conduction latencies (0.7-5 msec) compatible with those from orthodromic studies (fiber velocity 2.3msec -1) (Deniau et al., 1976; Anderson and Yoshida, 1977; Guyenet and Aghajanian, 1978; Deniau et al., 1978c). Moreover, projecting neurones were revealed to be localized exclusively to the SNR (55-80~o of cells recorded) (Deniau et al., 1976; Deniau et al., 1978d; Guyenet and Aghajanian, 1978) in agreement with the neuroanatomical data mentioned earlier. These antidromic stimulation studies also revealed that some nigro-thalamic neurones project bilaterally (11%) (Deniau et al., 1978c) and may send axon collaterals bilaterally to the superior colliculus and striatum (Anderson and Yoshida, 1977; Deniau et al., 1978c). Few intracellular studies have been devoted to the nigro-thalamic inputs though Frigyesi and Machek (1971) and Frigyesi (1975) described short latency EPSPs or longer

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latency EPSP-IPSP sequences in dorsal thalamic neurones (VA, VL, VM) following low-frequency stimulation of the rostral SN. Both relay and nonrelay VL neurones responded with a single spike from a small, short latency EPSP. A few cells, however, in the VA/VL showed a small, brief hyperpolarization without prior depolarization. Depolarizing potentials followed by prolonged hyperpolarization have also been reported in CM-PF neurones following SN stimulation (Krauthamer and Dalsass, 1978). On the other hand, SN stimulation was reported to evoke only short latency monosynaptic IPSPs in VL and VM neurones located ventrally to cerebello-thalamic relay neurones (Anderson and Yoshida, 1977; Ueki et al., 1977). Although the use of barbiturate anesthesia could possibly have masked any excitatory synaptic effects, these authors concluded that the nigro-thalamic pathway was inhibitory, and thalamic target neurones did not receive converging inputs from the cerebellum. The conclusions from these studies appear to indicate that the nigro--thalamic pathway is inhibitory and the short latency monosynaptic excitations observed may be a consequency of activation of cortico-thalamic fibers. However, the question concerning SN inputs to thalamic relay and nonrelay neurones is important and needs to be resolved. Nigro-thalamic neurones clearly appear to play a determining role in the control of excitability of the thalamus. Thus, Deniau et al. (1978c) conclude that SNR neurones, which exhibit a high level of spontaneous activity, exert a tonic inhibition on thalamic cells (see also Bendrups and McKenzie, 1974). Since nigro-thalamic cells may be activated by striatal stimulation (Deniau et al., 1976; Dray et al., 1976a; see also Section 6.3.1), thalamic activity could be phasically iraerrupted by strio-nigral influences (Frigyesi and Machek, 1971; Bendrups and McKenzie, 1974). Thus, SN projections to VL (middle and ventro-medial) in particular would be involved in controlling axial and proximal musculature since this area of the VL projects to cortical area six (Massion and Rispal-Padel, 1972a, b; Rispal-Padel and Grangetto, 1973). Little is known concerning the transmitter in the nigro-thalamic pathway. However, the finding that GAD activity is decreased in the superior colliculus following lesions of the SNR may be significant in this respect (Vincent et al., 1978). Since this finding suggests GABA as an inhibitory transmitter in the nigro-collicular pathway, nigrothalamic fibers would also be expected to use GABA since these fibers send collateral projections to the colliculi (Anderson and Yoshida, 1977; Deniau et al., 1978b). This has recently been confirmed by neurochemical data showing a significant reduction of GAD activity in the VM following kainic acid lesions or electrocoagulation of the substantia nigra (DiChiara et al., 1979). 6.2.2. N igro-br ainstem pathways Only with axon-transport techniques have nigro-brainstem pathways been convincingly demonstrated. Though earlier observations tentatively suggested the existence of a nigro-tectal pathway (Rioch, 1929; Carpenter and McMasters, 1964; Afifi and Kaelber, 1965) this was considered to be axons of passage from the cerebral cortex (Afifi et al., 1970). Nigro-brainstem fibers project.mainly ipsilaterally (contralateral projections also exist) to reticular formation, superior colliculus and the central periaqueductal grey substance, taking their source principally from medium and large cells of the SNR (Hopkins and Niessen, 1976; Rinvik et al., 1976; Jayaraman et al., 1977; Faull and Mehler, 1978; Graybiel, 1978; Grofova et al., 1978; Vincent et al., 1978). Nigro-reticular cells, however, appear to be found close to the ventral tegmental area of Tsai (Rinvik et al., 1976). Nigrotectal cells, forming the major pathway, appear to be aggregated within rostroventral and caudo-lateral regions of the SNR, where they form a conspicuous lamina immediately adjacent to the cerebral peduncle (Fig. 31) (Jayaraman et al., 1977; Faull and Mehler, 1978; Graybiel, 1978). These cells project mainly ipsilaterally to the caudal two thirds of the intermediate grey layer of the superior colliculus (Jayaraman et al., 1977; Faull and Mehler, 1978; Graybiel, 1978) where terminals collect to form a promi-

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nent regular banding or clumping pattern (Graybiel, 1978). There is also a modest contralateral nigro-collicular projection. The distribution of nigro-tectal fibers suggest that they may influence cells of the tecto-spinal tract, since these are also located in deeper layer of the superior colliculus (Kuypers and Maisky, 1975; Rinvik et al., 1976). Moreover, Graybiel (1978) discusses the possibility that the nigro-tectal pathway could transfer information from the visual cortices through a trans-striatal link to the superior colliculus. Indeed, Faull and Mehler (1978) emphasize the remarkable topographical correspondence in the visual and motor cortico-striato-nigral relays and suggest that a nigro tectal subnucleus conveys striatal information to the deeper "motor" layers of the superior colliculus. Neurons with "visual" and "motor" fields in the intermediate grey layer in fact discharge in a precisely time-locked fashion before saccadic eye movements (Schiller and Koerner, 1971; Wurtz and Goldberg, 1972; Sparks, 1975). In particular, neurones have been found which fire in readiness for visuomotor effects (Wurz and Goldberg, 1972; Mohler and Wurtz, 1976). Thus, activity in the nigro-tectal pathway, as in other basal ganglia regions (see Section 7.3), may be functioning in the preparation of motor responses. Significantly, a number of neurological disorders of the basal ganglia (e.g., P.D. and H.D.) are associated with signs of oculomotor and visuomotor disfunction, such as the initiation or performance of eye movements and inattention to stimuli in the visual field (Cogan, 1964; Mettler, 1964; Smith 1966; Starr, 1966, DeJong and Melvill-Jones, 1971; Melvill-Jones and DeJong, 1971; Corin et al., 1972; Bender, 1974; Denny-Brown and Yanagisawa, 1976; Shimizu et al., 1977). In addition, severe cell loss in the SN, superior colliculus and periaqueductal grey is found in progressive supranuclear palsy (Steele et al., 1964; Steele, 1972). 6.2.2.1. E l e c t r o p h y s i o l o g y and transmitters Nigro-tectal and nigro-tegmental projections have been confirmed in extracellular electrophysiological studies. Initially, York and Faber (1977) showed that a small number of tectal cells (26/228) were orthodromically activated by medial and lateral SN stimulation. More recently, short latency inhibition (considered to be monosynaptic) of neurones in the intermediate and inferior layers of the superior colliculus has been described following SN stimulation (Deniau et al., 1978a). These inhibitions were considered unlikely to result from activation of cerebral peduncle or optic-tract fibers, since stimulation of such fibers produced excitation in the superior coiliculus. Nigral evoked excitations were, however, observed in a small number of cells localized to the more dorsal layers of the colliculus. As in York and Faber's study, these cells could be activated by photic stimulation through the contralateral eye. Antidromic stimulation techniques have revealed that nigr~collicular fibers are slowly conducting (2.6 m/sec), have their source exclusively in the SNR and project bilaterally, though the ipsilateral projection is the more substantial (Anderson and Yoshida 1977; Deniau et al., 1977; Deniau et al., 1978c). Additionally, some nigro-collicular fibers also project to the thalamus and striatum (Anderson and Yoshida, 1977; Deniau et al., 1978b), Finally, Guynet and Aghajanian (1978) have shown that some SNR neurones can be antidromically activated by stimulation of the reticular formation (n. reticulo-pontis). While earlier findings suggested that the nigro-tectal pathway was facilitatory (York and Faber, 1977), more recent evidence indicated this pathway to be a monosynaptic inhibitory one (Deniau et al., 1978a). Indeed, such a conclusion would be in keeping with the fact that nigro-tectal fibers send inhibitory collaterals to the thalamus. Furthermore, biochemical and morphological evidence would support a nigro-tectal inhibitory projection. Thus, kainic acid lesions of the SN produced a significant reduction of GAD activity in the superior colliculus without affecting glycine concentrations, aspartate uptake or the activity of ChAT (Vincent et al., 1978a; DiChiara et al., 1979). Moreover, SN-collicular nerve terminals form symmetrical synapses with major dendrites and contain pleomorphic vesicles; a morphology similar to that of GABA containing terminals in other brain areas (Vincent et al., 1978a). However, the identity of the facilitatory

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transmitter in the sparse nigral projection to dorsal layers of the colliculus (Deniau et al., 1978a) deserves further attention. Caudally mediated effects of SN stimulation have been suggested to be DA mediated (Hassler and Wagner, 1975). This may be attributed to activation of nigro-reticular cells which have their source close to the ventral tegmental area of Tsai, corresponding to the DA cell group A10 (Dahlstrom and Fuxe 1965; Rinvik et al., 1976). More recently, however, evidence for an uncrossed spinal dopaminergic pathway originating in the SN has been reported (Commissiong et al., 1979). 6.2.3. Other nigral efferents Sparse projections to a variety of areas have been described anatomically, though these have rarely been investigated using electrophysiological methods. 6.2.3.1. Nigro-amygdaloid projection This pathway arises apparently from fusiform DA-containing neurones in the dorsal layer of the SNC (Fallon et ai., 1978), which project to the olfactory tubercle and amygdala. Also, Kaelber and Afifi (1977) have demonstrated projections from the lateral SN which traverse the GP and terminate in the lateral and central regions of the ipsilateral amygdala. Incidentally, the lateral extreme of the central amygdaloid nucleus has been considered to be a transition zone between the limbic and extrapyramidal systems (Hall, 1972). A nigral projection to this region appears to support this hypothesis. 6.2.3.2. Nigro-raphe projection Efferents to the rostra1 parts of the DRN have been described from the SNC and SNR (see fig. 6 of Sakai et al., 1977; Pasquier et al., 1977). Presently little else is known about this possible projection, though SN stimulation produced inhibition or excitation of raphe neurones located in the posterior midbrain and anterior pons (Stern et al., 1979). 6.2.3.3. Nigro-cortical projection A nigro-cortical pathway appears to project bilaterally, and since it takes its source from the SNC cells, may be DA-ergic (Llamas and Reinoso-S.uarez, 1969; Molina-Negro, 1969; Avendano et al., 1976). 6.2.3.4. Nigro-locus-coeruleus projection An ipsilateral projection mainly from cells of the SNR has been described to the ventrolateral locus coeruleus (Sakai et al., 1977). No further evidence concerning this pathway is known. 6.2.3.5. Nigro-cerebeilar projection The SNC appears to be the major source of nigral efferents to the cerebellum (interpositus, dentate, cerebellar cortex). Indeed, it is likely that the SNC may be the source of DA-axons to the cerebellum (Chan-PMay, 1977). 6.3. AFFERENT PATHWAYS OF THE SUBSTANTIA NIGRA The diversity of efferent pathways of the SN is adequately matched by that of its afferents. Probably the most important afferent influences on the SN come from the ipsilateral striato- and pallido-nigral projections. There are of course a multitude of other nigro-petal pathways whose influences are as yet uncertain (Fig. 27). 6.3.1. The striato-nioral projec|ion This pathway projects ipsilaterally through the GP to the SN (Rundles and Papez, 1937; Papez, 1941; Verhaart, 1950; Voneida, 1960; Szabo, 1962, 1967, 1970; Nauta and

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Mehler, 1966; Kemp, 1970; Kim et al., 1971; Hadju et al., 1973; Usunoff et al., 1974). It was considered to arise from some 5To of large striatal neurones with myelinated axons (Kemp and Powell, 1971b; Fox and Rafols, 1976). More recent studies, however, confirm that perhaps 30-50% of striatal neurones are output cells (Leontovich, 1954; Grofova, 1975; Bunney and Aghajanian, 1976a; Kanazawa et al., 1976; B a k e t al., 1978), and that a significant proportion are the spiny, medium size neurones with fine-caliber fibers (DiFiglia et al., 1976; Kocsis et al., 1977a) which do indeed project to the SN (Somogyi and Smith, 1979). The striato-nigral pathway has a precise topographical arrangement such that in general the head of the caudate projects to the rostral third of the SN with a mediolateral correspondence. Fibers from the putamen project to the caudal two-thirds of the SN with the dorsal putamen relating to lateral parts of the SN and ventral regions relating to medial parts of the SN (Voneida 1960; Szabo, 1962, 1965, 1970; Nauta and Mehler, 1966; Niimi et al., 1970; Usunoff et al., 1974; Carpenter, 1976a, b). Although in rodents the caudate appears to innervate all parts of the SN, the heaviest innervation originates from the tail of the caudate (Bunney and Aghajanian, 1976a). In particular, strio-nigral fibers terminate mainly in the SNR (Grofova and Rinvik, 1970; Kemp, 1970; Hattori et al., 1975), while pallido-nigral projections terminate in both the SNR (from GPE) and SNC (from GPI) (Grofova, 1975; Hattori et al., 1975; Bunney and Aghajanian, 1976a; Kim et al., 1976; Carter and Fibiger, 1978). It is likely that most strio- and pallido-nigral fibers make axodendritic synapses in the SN (Grofova and Rinvik, 1970; Schwyn and Fox, 1974), though in rodents axosomatic boutons appear to be more common (Hajdu et al., 1973; Hassler et al., 1975). 6.3.1.1. Electrophysiology and transmitter identity Electrophysiological studies support the concept of a long monosynaptic strio-nigral pathway. In general, stimulation of the ipsilateral caudate reduces neuronal activity in the SN (Frigyesi and Purpura, 1967; Feltz, 1971b; Goswell and Sedgwick, 1971; Yoshida and Precht, 1971; McNair et al., 1972; Crossman et al., 1973; Feger and Ohye, 1975; Frigyesi and Szabo, 1975; Dray et al., 1976a) (Fig. 33). Moreover, evoked activity shows 30

I

AiilillEZ

25

'H

FI

D

H ~ 20

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5 0

DISTANCE (mrn ) FIG. 33. Extra and intracellular responsesof substantia nigra cells evoked by caudate stimulation. A, Extraeellularlyrecorded spontaneous discharges of a nigral cell. B, Inhibition of the same cell as in A concomitant with a positive field potential evoked by caudate stimulation. C, Caudate evoked IPSP in a nigrai ceil. A depolarization is seen following the EPSP. D, extracellular control for C. E, IPSP evoked by stimulation of the cerebral peduncle in the same cell as in C. F. extracellular control for E. G-H, caudate-evokedpotentials average by computer (16 sweeps). H, net IPSP obtained by subtracting extracellular response (upper trace in G) from the intracellular response (lower trace in G). I, latency of IPSPs plotted against distance between stimulating and recording sites. A regression line intercepts the Y axis at 0.8 msec suggesting a single synaptic delay. (From Yoshida and Precht, 1971; reproduced with permission.)

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FtG. 34. Different types of responses in substantia nigra (SN) following stimulation of the caudate nucleus (Cd) (arrows or vertical bars correspond to the time of stimulation). Responses are shown in oscilloscope records (upper traces) and raster dot-display (lower records). In the uppermost part of the dot-display the spontaneous activity is shown. A, cell with inhibition only during which a field potential is recorded. B, cell with excitation followed by inhibition and rebound excitation. Note different time bases in A and B. (From Feger and Ohye, 1975; reproduced with permission.)

a topographical relationship with the stimulation site (Goswell and Sedgwick, 1970; Frigyesi and Purpura, 1967; Frigyesi and Szabo, 1975). Although it has been argued that the use of barbiturate anesthesia favored the appearance of inhibitory responses in the SN (McNair et al., 1972), similar effects have been observed in unanesthetized preparations (e.g., Feger and Ohye, 1975). Barbiturate anesthesia does, however, prolong synaptic inhibition in the SN as in other brain areas (e.g., Dray et al., 1976a). In addition to the inhibition of SN neurones, caudate stimulation has been shown to evoke excitation in the SN and produce EPSP-IPSP sequences during intracellular studies (Frigyesi and Purpura, 1967; Feltz, 1971b; Frigyesi and Szabo, 1975; Feger and Ohye, 1973; Dray et al., 1976a). This facilitatory effect has been attributed to spread of stimulus current with possible activation of cortico-fugal fibers (Goswell and Sedgwick, 1971 ; Purpura, 1975) while the lack of such effects have been considered to be due to the use of barbiturate anesthesia (Feger and Ohye, 1975). However, striatal evoked excitation in the SN was still observed in lightly anesthetized or unanesthetized preparations even with careful controls for stimulus spread (Feger and Ohye, 1975; Dray et al., 1976a) (Fig. 34). Thus, electrophysiological studies suggest that there are two distinct, slowly conducting (1 m/sec), monosynaptic pathways from the striatum to the SN. This conclusion is supported by anatomical studies showing two types of synaptic terminals in the SN with origins in the striatum (Grofova and Rinvik, 1970; Kemp and Powell, 1971a; Schwyn and Fox, 1974). In addition, however, Frigyesi and Szabo (1975) suggest that the strio-nigral pathway comprises three distinct projections. Two produce either a short latency EPSP or IPSPs (compatible with the pathways discussed above), while the third gives rise to longer latency IPSPs in the SN. Although there is presently reasonable evidence for an inhibitory and an excitatory striato-nigral transmitter, the possibility of another inhibitory transmitter remains uncertain. It may, however, be that two inhibitory pathways use the same transmitter, or that some effects of caudate stimulation result from activation of nigro-striatal fibers which give off collaterals back to the SN (e.g. see Rinvik and Grofova, 1970; Schwyn and Fox, 1974; Wilson et al., 1977), though these have not always been confirmed (e.g., Juraska et al., 1977).

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6.3.1.2. I d e n t i t y o f striato--nigral t r a n s m i t t e r Pharmacological studies identifying the striato-nigral inhibitory transmitter have certainly been more convincing than the corresponding studies of the nigro-striatal pathway. These studies support the neurochemieal data suggesting that GABA serves this role. Thus, the SN contains the highest concentration of GABA of any part of the nervous system (Fahn and Cote, 1968; Okada et al., 1971; Kim and Hassler, 1975: Balcom et al., 1975; Fahn, 1976; Nitsch and Okada, 1976), which appears, with its synthesizing enzyme GAD, to be localized to nerve terminals (MeGeer et al., 1971; Fonnum et al., 1974; Ribak et al., 1976). Lesion studies further suggest that GABAcontaining terminals originate from neurones in the ipsilateral striatum and globus pallidus (McGeer et al., 1971; McGeer et al., 1973; Hattori et al., 1973; Fonnum et al., 1974; Kataoka et al., 1974; McGeer et al., 1974; Streit et ai., 1979), though the pallido-nigral GABA pathway appears to be minor compared with that from striatum (Fonnum et al., 1978). Additionally, strio-nigral GABA terminals are confined to the dendritic processes of the SNR, while those from the pallidum appear to have a greater distribution within the SNC on DA-ergic cell bodies (Hattori et al., 1975; Ribak et al., 1976). GABA and GAD distribution within the SN appears to be uneven, being highest in the SNR, especially in the medial SNC-SNR border, and decrease in a mediolateral direction. Additionally, their concentrations are higher in rostral SN and even more caudally (Fonnum et al., 1974; Kanazawa and Toyokura, 1975; Tappaz et al., 1976; Tappaz et al., 1977). However, extensive lesions of GABA afferents or destruction of nigral cell bodies with kainic acid do not entirely abolish SN, GAD activity (Hattori et al., 1973; Fonnum et al., 1974; Kataoka et al., 1974; McGeer et al., 1974; Storm-Mathisen, 1975; Nagy et al., 1978c), which suggests that some GAD may be localized in SN neurones or other afferent terminals. Indeed, GABA-containing SN neurones may be intrinsic or may give rise to a nigral efferent pathway (Wolman, 1971; Robinson and Wells, 1973; Dray and Straughan, 1976, 1978; Nagy et al., 1978c). In keeping with a neurotransmitter function for GABA in the SN, both electrical and K ÷ stimulation has been shown to evoke a Ca2+-dependent release of GABA from nigral slice preparations (Okada and Hassler 1973; Reubi et al., 1977). Also, electrical stimulation of the striatum or globus pallidus increases 3H-GABA release from the SN (Kondo and Iwatsubo, 1978), enhances the loss of GABA following inhibition of synthesis (Swift et al., 1978), and increases GABA turnover without changing GABA levels (Bertilsson et al., 1977; Mao et al., 1978). Finally, receptor binding studies show that 3H-GABA binds avidly to SN membrane preparations by a Na÷-independent process, suggesting that binding occurs specifically on postsynaptic sites (Enna et al., 1975; see also Section 2 for neurological disease data). Both bicuculline and picrotoxin, but not strychnine, administered systemically or by microelectrophoresis reduced the caudate-evoked positive field-potential (taken to be an index of the outward flow of inhibitory postsynaptic current), as well as the inhibition of cell firing in the SN (Precht and Yoshida, 1971; Crossman et al., 1973; Dray et al., 1976a) (Fig. 35). Similarly, locally administered tetanus toxin (which prevents presynaptic release of GABA) prevented caudate evoked inhibition in the SN, but not the inhibitory effects of microelectrophoretic GABA or monoamines (Davies and Tongroach, 1977, 1979). However, striatal evoked inhibition in a few SN neurones was resistant to bicuculline, though the effects of extrinsic GABA were always suppressed (Dray et al., 1976a). This raises the possibility, discussed by Frigyesi and Szabo (1975), of a second type of bicuculline-insensitive striato-nigral inhibition. However, it may be that some nigral neurones may be inhibited by intrinsic SN circuits, also activated by caudate stimulation. The identity of the striato-nigral excitatory transmitter is unknown, though it appears not to be ACh or an excitant amino acid since such synaptic excitations were resistant to electrophoretic atropine or D-aminoadipate (Dray, unpublished; Collingridge and Davies, 1979). On the other hand, the polypeptide substance P has been speculated to be a strio-nigral transmitter (Dray and Straughan, 1976, 1978). The concentration of this

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Micro-iontophoresis

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PSTH •

Evoked potential

Caudate stim.

GAB,,,mA GIr~ycine m, ~

10

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~.1500 pV

rain

50 msec

m

=== ,,-- ===

i10m~~ll i i20nA

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Bicuculine methochloride 20 n A

Recovery (2 rain)

FIG. 35. Effectsof electrophoreticbicucullinemethochloride(BMCJ on the inhibitory responses of a spontaneouslyfiring substantia nigra neurone to GABA and glycine;and on evoked inhibition produced by caudate stimulation, Left, continuous trace (spikes per second against time) shows reproducible depression of firing by GABA (10 nA) and glycine(15 nA). Middle, PSTH from the same neurone (200 sweeps, duration 500 msec) showing inhibition preceded by brief excitation and followedby rebound excitation. Right, caudate evoked field-potentialcomprising a positive phase corresponding with the period of neuronal inhibition and a negative phase corresponding with rebound excitation. The administration of BMC (20 nAj selectively abolished the effect of GABA (left middlel and reduced caudate evoked (centre middlel inhibition as well as the amplitude of the evoked positive field potential (centre right). Recoveryof responsivenessis shown on bottom traces. (From Dray et al., 1976a, reproduced with permission.) peptide in the SN is higher than any other brain region, being particularly concentrated in the SNR (Powell et al., 1973; Brownstein et al., 1976; Kanazawa and Jessell, 1976; Mroz et al., 1977a, b; Cuelio et al., 1978; Gauchy et al., 1979) with fibers occurring most profusely in the SNC at rostral levels and in the SNR at caudal levels (Cuello and Kanazawa, 1978; Ljungdahl et al., 1978) in close proximity to DA cells and dendrites (Ljungdahl et a/., 1978). Additionally, the localization of substance P in nerve fibers and synaptosomal fraction (Duffy et al., 1975; Nilsson et al., 1974) and the demonstration of a Ca2+-dependent release from in vitro SN slices further suggest a possible neurotransmitter function (Jessell, 1978; Cuello et al., 1978; Reubi eta/., 1977). In keeping with this hypothesis, substance P can excite SN neurones (Davies and Dray, 1976; Walker et al., 1976). Finally, lesion studies suggest that nigral substance P originates from cells in the ipsilateral striatum and G P with a major contribution arising from neurones in the anterior striatum (Hong et al., 1977b; Jessell et al., 1977; Kanazawa et al., 1977; Mroz et al., 1977a, b; Paxinos et al., 1978). These substance-P fibers are distinct from striatonigral GABA fibers, having a different striatal origin and different nigral distribution (Gale et al., 1977; Cuello et al., 1978). Interestingly, GABA may inhibit the K+-stimu lated in vitro release of substance P from SN slices, and has thus been speculated to be involved in regulating its release in vivo (Jessell, 1977). Ample circumstantial evidence for an excitatory strio-nigral substance-P pathway exists, though pharmacological verification is yet lacking. Lioresal (fl-parachlorophenylGABAI was suggested as a substance-P antagonist drug (Saito et al., 1975) and may reduce substance-P excitation of nigral neurones, but this action was clearly unselective (Davies and Dray, 1976). Thus, the identification of the striato-nigral excitatory transmitter must await the development of more selective antagonists. 6.3.2. Pallido-nigral p a t h w a y As discussed above, there is ample evidence for pallido-nigral projections terminating both in the SNC and SNR (Nauta and Mehler, 1966; Grofova, 1975; Hattori et al., 1975;

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Bunney and Aghajanian, 1976a; Kanazawa et al., 1976; Kim et al., 1976; Carter and Fibiger, 1978). This appears to comprise a GABA-ergic projection (McGeer et al., 1973; McGeer et al., 1971; Hattori et al., 1973; McGeer et al., 1974; Fonnum et al., 1978), and in all probability one containing substance P (Kanazawa et al., 1977; Hong and Costa, 1977b; Mroz et al., 1977a, b; Cueilo et al., 1978). Electrophysiological and pharmacological identification of discrete pallido-nigral projections is lacking. Such experiments would of course be complicated by concomitant activation of strio-nigral fibers traversing the GP.

6.3.3. R a p h e - n i g r a l projection Anatomical studies clearly show the existence of projections to the SN from the dorsal and medial raphe nuclei (Conrad et al., 1974; Bak et al., 1975; Bunney and Aghajanian, 1976a: Kanazawa et al., 1976; Pierce et al., 1976; Bobillier et al., 1976; Fibiger and Miller, 1977). It is probable that many raphe-nigral projections are in fact collaterals of raphe-striatal fibers (Poirier et al., 1969; van der Kooy and Hattori, 1979). Since .these raphe nuclei comprise the serotonin-containing B7-8 cell groups (Dahlstrom and Fuxe, 1964), it would seem likely that the raphe-nigral pathways might use 5HT as the neurotransmitter (Streit et al., 1979). In keeping with such a hypothesis, both 5HT and tryptophan hydroxylase are present in the SN localized mainly within the SNR to dense core vesicles of fiber terminals which make contact with DA neurones and dendrites (Fuxe, 1965; Kim et al., 1970; Fahn et al., 1971; Parizek et al., 1971; Hadju et al., 1973; Lloyd and Hornykiewicz, 1974; Palkovits et al., 1974; Brownstein et al., 1975; Reubi and Emson, 1978). Additionally, lesions of the raphe significantly lower SN tryptophan hydroxylase activity and 5HT content (Kuhar et al., 1972; Dray et al., 1976c; Fibiger and Miller, 1977; Palkovits et al., 1977; Dray et al., 1978; Reubi and Emson, 1978). Moreover, a K÷-evoked, Ca 2 ÷-dependent. release of 5HT has been demonstrated from SN slices, which was significantly reduced following chronic raphe lesions (Reubi and Emson, 1978). Electrophysioiogical studies revealed that the raphe-nigral projections were monosynaptic with slowly conducting fibers (0.2-1.0 m/sec) (Dray et al., 1976c, 1978). Additionally, raphe stimulation (DRN or MRN) evoked inhibition in the majority of SN neurones tested (Dray et al., 1976c; Fibiger and Miller, 1977), though some neurones were also excited. However, the correlation of raphe evoked inhibition and the predominantly inhibitory effects of microiontophoretic 5HT supported the concept of an inhibitory serotoninergic projection (Dray et al., 1976c). On the other hand, microiontophoretic 5HT was also seen to excite nigral neurones (Dray et al., 1976c, 1978; Aghajanian and Bunney, 1975), suggesting that 5HT receptors in the nigra were heterogeneous. Thus, present data suggests that there exists an inhibitory raphe-nigral projection using 5HT as a neurotransmitter. However, the fact that some raphe evoked excitations are seen in SN neurones, plus the evidence that cell bodies of the raphe contain putative transmitters other than 5HT (Moore and Halaris, 1975; Jacobs et al., 1978; Hokfelt et al., 1978), would indicate that the raphe-nigral pathway may in fact comprise mixed inhibitory and facilitatory fibers. Obviously, further studies are required, particularly those employing intracellular recording techniques. Indeed a preliminary report (Karabelas and Purpura, 1979) suggests that most orthodromic responses in the SN following DRN stimulation consist of EPSPs. Finally, pharmacological studies support the existence of an inhibitory raphe-nigral pathway which uses 5HT rather than an inhibitory amino acid like GABA. Thus, the 5HT-receptor antagonist, methiothepin, blocked both the inhibition by 5HT and that produced synaptically by raphe stimulation (Dray and Oakley 1977), while pretreatment with pCPA blocked the inhibitory effects of raphe stimulation (Fibiger and Miller, 1977). Neither bicuculline nor tetanus toxin affected raphe evoked inhibition (Dray and Straughan, 1978; Davies and Tongroach, 1978, and unpublished).

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6.3.4. Locus-coeruleus-nioral projection Though afferents from the locus coeruleus to the SN have not been successfully demonstrated (e.g., Cederbaum and Aghajanian, 1978), there exists circumstantial evidence for a NA-ergic projection from this region to the SN. Thus, the SN contains NA terminals, 3H-NA may be taken up into nigral neurones (Gulley and Smithberg, 1971; Sotelo, 1971; Farley and Hornykiewicz, 1977), and microelectrophoretic NA may effect SN cells, those in the SNC being depressed while those in the SNR may be depressed or excited (Crossman et al., 1974; Dray and Straughan, 1976). More recently, K+-stimu lated, Ca 2 +-dependent release of aH-NA has been demonstrated from SN slices, and this may be reduced by prior 6-OHDA lesions of the locus coeruleus. In addition, electrical stimulation of the ipsilateral locus coeruleus evoked long latency excitation-inhibition sequences from SN neurones, mainly from those in the SNC, suggesting that the projection may comprise mixed fibers (Collingridge et al., 1979). 6.3.5. Subthalamo-nigral projection Though a subthalamo-nigral pathway has been suggested from conventional anatomical studies following lesions of the STN (Glees and Wall, 1946; Whittier and Mettler, 1949a) this projection has more recently been confirmed using axon transport of HRP (Kanazawa et al., 1976). E!ectrophysiological studies have confirmed that STN cells send axon branches to both pallidal segments and to the substantia nigra (Deniau et al., 1978b; Hattori and Van der Kooy, 1979). However, no evidence was obtained for nigroSTN projections (Hammond et al., 1978). Additionally, stimulation of the STN produced orthodromic excitation, mainly in the SNR, though SNC cells were also activated (Hammond et al., 1978). In this study all substantia nigra cells were also inhibited, though this was considered to result from activation of striato-nigral fibers. There is presently no evidence concerning the transmitter identity of the subthalamo-nigral pathway. 6.3.6. Nucleus accumbens-nigral projection Both lesion and axoplasmic transport studies have revealed that the nucleus accumbens sends afferent projections ipsilatcrally to the SN (Swanson and Cowan, 1975; Conrad and Pfaff, 1976; Powell and Leman, 1976; Williams et al., 1977; Nauta et al., 1978). These fibers project topographically and terminate both in the SNC and SNR (Swanson and Cowan, 1975; Nauta et al., 1978). Some electrophysiological confirmation for this pathway exists, since stimulation of the medial accumbens produced either inhibition or facilitation of neurones located medio-caudally within the SNC-SNR border (Dray and Oakley, 1978), suggesting the presence of mixed projecting fibers. The identity of the transmitters in this pathway are presently unknown, though the inhibitory transmitter appears likely to be GABA. Thus, although lesions of the accumbens produced no changes in SN GABA concentration (Dray and Oakley, 1978) a recent report suggests nucleus accumbens evoked inhibition in the cat SN was attenuated by systemically administered bicuculline but not by strychnine (Fung et al., 1979). The topography and sparsity of fibers in this projection indicate that more detailed analysis is still required. However, the accumbens-SN projection does afford another route by which "limbic" areas can influence the integration of activity within the basal ganglia (see also discussion of GP, Section 4.2.3). 6.3.7. Cortico-niffral projection Abundant projections from cortical areas to the SN have been assumed (Vcrhaart and Kennard, 1940; Mettler, 1947a; Levin, 1949), though it appears that cortico-fugal fibers were modest in number and many only traverse the SN to other terminations (Rinvik, 1966; Afifi et al,, 1970). However, an electron microscopic study of Rinvik and Walberg (1969) revealed that the SN probably does not receive a direct projection from the cat cerebral cortex (see also Goswell and Sedgwick, 1973). On the other hand, direct ¢ortico J.P.~. 14/4-

e

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nigral projections have been reported (Bunney and Aghajanian, 1976a) and terminate in the medio-lateral SNC, SNL and to a lesser extent the SNR (Afifi et al., 1974). No electrophysiological evidence is available to confirm the projection. 6.3.8. Cerebello-nigral projection Degenerating terminals have been observed in medial and dorsal SN (mainly SNC) following lesions of the contralateral cerebellar nuclei (interpositus and dentate). Projections from the fastigial nucleus were sparser and no projections were observed from the cerebellar cortex (Snider et al., 1976). 6.4. NEUROPHARMACOLOGY OF THE SUBSTANTIA N1GRA 6.4.1. Dopamine in substantia nigra Besides the high content of GABA and substance P, which appear to be involved in striato-nigral transmission, the SN contains a number of other putative transmitters (see Table 4). These also seem to be important in regulating SN activity, particular attention being given to their interactions with the DA-ergic system. Within the SN itself, DA appears to have a significant function in addition to that of a nigro-striatal transmitter. As expected, the bulk of SN DA is contained in the SNC, but approximately one third is found in the SNR (e.g., Fahn, 1976), mainly within SNC-cell dendrites, other SNR DA-containing neurones and possibly in DA-axon collaterals. DA release seems likely to occur from the extensive dendritic processes of DA neurones which arborize extensively within the SNR (Bjorklund and Lindvall, 1975; Sladek and Parnavelas, 1975). These dendrites are varicose, contain clusters of small vesicles as well as large dense core vesicles, and are able to take up DA (Parizek et al., 1971; Hajdu et al., 1973; Bjorklund and Lindvall, 1975; Pickel et al., 1975). Additionally, both electrical or K ÷ depolarization stimulates a Ca2+-dependent release of DA from these structures and increases the concentration of the DA metabolites, HVA and DOPAC (Korf et al., 1976; Geffen et al., 1976). The mechanism of DA release from SN dendrites may, however, differ from that of nerve terminals in the striatum. Thus, DA in SN dendrites appears to be stored in the smooth endoplasmic reticulum, in contrast to predominantly vesicular sites of storage in axon terminals (Cuello and Iversen, 1978; Hattori et al., 1979b). Moreover, some SN dendrites have been shown to be in apposition to each other, though the plasma membranes appeared not to display synaptic specializations (Cuello and Iversen, 1978; but see also Hattori et al., 1979b). Additionally, tetrodotoxin (which suppresses nerve impulse flow and thus transmitter release by blocking Na + ionophores) reduced striatal DA release but not that from the SN (Nieoullon et al., 1977b). DA reuptake processes also exhibited differential pharmacological sensitivity; those in SN dendrites being blocked by both desipramine and benztropine, while those in striatal terminals only by benztropine (Bjorklund and Lindvall, 1975). As in the striatum, DA may stimulate SN adenylate cyclase activity, particularly in the SNR, and this effect may be blocked by neuroleptic drugs (Kebabian and Saavedra, 1976~ Phillipson and Horn, 1976; Traficante et al., 1976). However, these cyclase-linked DA receptors appear not to be localized to DA-neurones since adenylate cyclase activity remains after intranigral injections of 6-OHDA, but disappears after brain hemisection between the SN and striatum or following lesions of the descending striato-nigral projection. Thus, it is likely that the DA-sensitive cyclase is located on terminals of striatonigral fibers (Kebabian and Saavedra, 1976; Premont et al., 1976; Gale et al., 1977b: Phillipson et al., 1977; Spano et al., 1977; Quik et al., 1979), whereas DA-receptors recognized from binding studies are located on SN-DA neurones (Nagy et al., 1978b; Quik et al., 1979) (see Fig. 18). Interestingly, DA or amphetamine may stimulate the release of 3H-GABA from SNslice preparations, and this action may be blocked by neuroleptic drugs (Reubi et al., 1977). It is thus tempting to speculate that intranigral release of DA may be involved in a

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local inhibitory feedback circuit, regulating GABA release from striato-nigral fibers. The release of dendritic DA in the SN may have additional physiological functions and produces reciprocal changes in DA release from the striatum, This fact has been illustrated using push-pull cannulae techniques and measuring 3H-DA release (newly synthesized from 3H-tyrosine) from the caudate and SN following electrical or physiological stimulation of connecting systems. For example, unilateral stimulation of cortical areas four (motor) or eighteen and nineteen (visual) produced a long-lasting release of 3H-DA from the ipsilateral SN. These stimuli also produced a release of 3H-DA from the caudate nuclei (Nieoullon et al., 1978a). On the other hand, stimulation of the cerebellar dentate nucleus produced a decrease in 3H-DA release from the contralateral SN, but an increase from the ipsilateral SN. These effects were accompanied by corresponding opposite changes in DA release from the caudate nuclei (Nieoullon et al., 1978b). Similarly, fastigial stimulation only decreased DA release from the ipsilateral SN but increased it in the corresponding caudate. These experiments are of particular significance, since they indicate that the release of DA in the nigro-striatal systems of both sides of the brain are interdependent. Indeed, the administration of DA into one SN reduces 3H-DA release in ipsilateral caudate, increases it in the contralateral caudate, but reduces it in the contralateral SN. Similar reciprocal changes in 3H-DA release were seen following unilateral peripheral or visual stimulation (Nieoullon et al., 1977a, 1977b, 1977c). Additionally, these studies of nigro-striatal DA changes amplify apparent inconsistencies found during unilateral manipulations of the nigro-striatal system. Thus, ipsilateral lesions of the striatum produced an acute increase in DA concentration on the contralateral side, while chronic ipsilateral lesions decreased DA concentration in both caudate nuclei (ChanduLall et al., 1970). Moreover, lesions of the MFB or the SN which produce a significant reduction of ipsilateral striatal DA concentration either leave unchanged or increase the firing of neurones in this striatum, but produce a profound reduction in neuronal firing in the contralateral striatum (Hull et al., 1974; Levine et al., 1977). Although transcallosal-caudate-caudate connections have been described (Mensah and Deadwyler, 1974) these appear to be too sparse to account for the contralateral changes described above. Since the direct connections of the nigra and striatum appear to be strictly unilateral it is likely that the changes in DA release observed were mediated indirectly. Within the SN, microelectrophoretic studies have shown that DA or DA agonists inhibit the activity of DA-ergic neurones in the SNC, whereas neuroleptic administration increases it (Aghajanian and Bunney, 1974; Bunney and Aghajanian, 1976b; Bunney et al., 1973a; Bunney et al., 1973b). However, cells in the SNR were considered to be relatively insensitive to DA, though many could certainly be excited or depressed (Aghajanian and Bunney, 1975; Dray and Straughan, 1976; Dray et al., 1976c). Additionally, nigral dopaminergic cells appear to be considerably more sensitive to DA than neurones in caudate (Skirboll et al., 1979). The effects of DA, either excitatory or inhibitory may be antagonized by neuroleptics (Bunney et al., 1973; Aghajanian and Bunney, 1974; Dray et al., 1976b) and nigral DA receptors appear to be distinct from ct- or fl-adrenoceptors (Aghajanian and Bunney, 1977). Interestingly, acute neuroleptic administration increases the firing of SNC-DA neurones but chronic neuroleptic treatment suppresses spontaneous firing, This was suggested to result from a chronic depolarizing block (Bunney and Grace, 1978). The DA neurones of the SNC and neurones in the SNR appear to be distinctive in terms of their spike configuration and firing patterns. Thus, DA neurones which are sensitive to DA-ergic agonists appear to have wide action potentials and a slow-bursting or regular firing pattern (Aghajanian and Bunney, 1974; Bunney et al., 1973; Rebec and Groves, 1975; Dray et al., 1976a; Wilson et al., 1977b; Guyenet and Aghajanian, 1978). These criteria have been considered sufficient to identify the DA cells of the SN. Cells mainly within the SNR are characterized by narrower action potentials and a more regular firing pattern (Dray et al., 1976a; Guyenet and Aghajanian, 1978), though cells with burst-firing patterns may also be observed and may be nigral interneurones (Dray et al., 1976a; Wilson et al., 1977b).

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6.4.1.1. Doparaine "'autoreceptors" The release of DA from dendrites in the SN has been postulated to activate DA "autoreceptors" located on DA-ergic neurones or their dendrites and provide a mechanism of self-inhibition or regulation of DA-ergic cell activity (Aghajanian and Bunney, 1974; Groves et al., 1975: Wilson et al., 1977a; Wilson et al., 1977). Such an action would be expected to reduce the release of DA from nigro-striatal terminals (Nieoullon et al., 1977a; Maggi et al., 1978). This mechanism has recently been proposed to account for the changes in DA metabolism produced by drugs acting on DA receptors. Thus, neuroleptics (which block DA-receptors postsynaptically) increase DA synthesis and increase cell firing in the SNC and in the striatum, while DA-receptor agonists produce the opposite effects (for refs see Aghajanian and Bunney, 1974; Groves et al., 1975). These changes have, however, also been considered to be secondary to either the blockade or activation of striatal postsynaptic DA-receptors and mediated through a feedback loop from the striatum which impinges on nigral DA-neurones (Carlsson et al., 1972; Carlsson and Lindqvist, 1963) or by the presynaptic regulation of DA release through actions on striatal DA-ergic terminals (Christiansen and Squires, 1974; Iversen et al., 1976). The latter hypothesis was considered unlikely, since DA-ergic drugs did not effect 3H-DA release from superfused synaptosomal preparations and that neither the release of DA recaptured by uptake processes nor that newly synthesized from tyrosine was regulated by a negative feedback involving presynaptic receptors (Raiteri et al., 1978). Thus, the amounts of DA released into the synaptic regions appear to be regulated indirectly at the TOH level through changes in synthesis rate; short-term adjustments being mediated by changes in enzyme specific activity, while long-term adjustments involve shifts in the availability of the enzyme (see Roth et al., 1974; Schlehuber et al., 1975). The feedback-loop hypothesis also seems unlikely since selective lesions of the strionigral pathway did not modify the response of the DA-system to neuroleptics (GarciaMunoz et al., 1977). Moreover, unilateral injections of kainic acid into the striatum which destroyed postsynaptic DA-receptors and strio-nigral projecting neurones did not modify the changes in DA metabolism produced by neuroleptics or DA agonists (DiChiara et al., 1977b: DiChiara et al., 1977c). Thus, the intranigral DA "autoreceptor hypothesis" appears to describe an important mechanism for regulating nigral and striatal DA-ergic activity. Preliminary studies suggest, however, that intranigral injections of DA agonists o r antagonists produce no measurable behavioral changes (Glick and Crane, 1978). Thus, the expression of behavior through changes in nigral DA-metabolism appear unclear at present. 6.4.2. N A in substantia nigra Although as mentioned previously, in Section 6.3.4, NA may affect the activity of SN neurones its precise role in the SN is not understood. While the source of NA terminals of the SN may derive from the locus coeruleus (Collingridge et al., 1979) no attempts have been reported correlating the effects of NA with those of stimulation. Unilateral lesions of the locus coeruleus or the ventral NA-ergic bundle, however, produce contraversive circling following the administration of DA-ergic stimulants (Pycock et al., 1975; Donaldson et al., 1978). This manipulation also increased ipsilateral striatal DA levels, but no measurements of DA turnover were performed to indicate more accurately possible changes in nigro-striatal DA-ergic activity. However, the results are suggestive of the possibility that synaptically released NA may in fact facilitate nigro-striatal DA-ergic transmission (Donaldson et al., 1978; Collingridge et al., 1979). 6.4.3. 5 H T i n substantia nigra The serotonin system of the SN, as discussed in Section 6.3.3, appears to derive principally from the midbrain raphe nuclei. The raphe-nigral input appears to be tonically inhibitory on DA neurones, since raphe lesions which lower the SN 5HT concentration produce an increase in nigral DA turnover (Dray et al., 1978; Giambalvo and

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Snodgrass, 1978; Nicolaou et al., 1979). In keeping with this, unilateral microinjections of 5HT into the SN produced ipsiversive circling behavior, indicative of a unilateral reduction in nigro-striatal DA-ergic activity. This behavior was accompanied by a decreased striatal DA-release and was abolished by haloperidol pretreatment. Conversely, intranigral injections of methysergide (a 5HT receptor blocker) or the neurotoxin 5,7,-DHT produced opposite effects to those of 5HT (Straughan and James, 1978). Similarly, unilateral lesions of the raphe caused spontaneous contraversive circling which could be intensified by DA-ergic agonist administration (Costall and Naylor, 1974; Costall et al., 1976b). On the other hand, Nicolaou et al. (1979) suggest that raphe lesions produce differential effects on turning behavior. Thus, both apomorphine and amphetamine induced ipsiversive turning in unilaterally DRN-lesioned rats, but contraversive turning after MRN lesions. 6.4.4. G A B A in substantia nigra From the discussion in Section 6.3.1.2, the striato-nigral projection is believed to utilize GABA as a neurotransmitter, and activation of this pathway inhibits neuronal activity both in the SNC and SNR. In keeping with this, local administration of GABA or GABA-mimetic agents onto SNC or SNR neurones inhibits their activity by a bicuculline or picrotoxin sensitive processes (Feltz, 1971b; Crossman et al., 1973; Aghajanian and Bunney, 1974; Dray et al., 1976a; Olpe and Koella, 1978). Moreover, cells of the SNR have been described to be more sensitive to the effects of GABA than those in the SNC (Aghajanian and Bunney, 1975; Dray et al., 1976a). On the other hand, the structural analogue of GABA, fl-p-chlorophenyl-GABA (lioresal) also depressed SN neurone activity, but its actions were resistant to bicuculline (Olpe et al., 1977). Many studies have been devoted to exploring the relationship of the GABA system with the nigral DA-ergic system. Thus, local unilateral microinjections of picrotoxin into the SN produced an increase in the release of 3H-DA from the ipsilateral striatum and contraversive circling behavior, suggesting that the nigro-striatal DA-system had been activated as a result of the blockade of endogenous SN GABA activity (Tarsy et ai., 1975; Cheramy et al., 1977a; Wolfarth et al., 1979; but see also Martin et al., 1978). On the other hand, unilaterally increasing GABA octivity in the SN by !nhibiting its metabolism (e.g., with a GABA-T inhibitor) or by the injection of GABA-mimetic drugs also produces an increase in SN DA-neurone activity, an increase in striatal DA-release and contraversive circling behavior (Dray et al., 1975; Dray et al., 1977; Oberlander et al., 1977; Scheel-Kruger et al., 1977; Olpe et al., 1977; Cheramy et al., 1978a; Koob et al., 1978; Martin and Haubrich, 1978; Martin et al., 1978; Palfreyman et al., 1978). Moreover, GABA may facilitate the K +-stimulated release of 3H-DA from nigral slices (Starr, 1978), These latter findings certainly appear paradoxical and imply that the effects of GABA mimetics on nigral DA neurones may be mediated indirectly within the SN, possibly through the involvement of inhibitory non-GABA-releasing interneurones (see Dray and Straughan, 1976; Francois et al., 1979). The effects of GABA appear to depend particularly on the site of microinjection within the SN. Thus, when manipulations were confined to the SNR region, activation of the DA system results, but injections into the SNC region produced the expected decrease in DA cell activity (Anden and Stock, 1973; Dray et al., 1977; Racagni et al., 1977). Indeed, a differential action of the GABA-mimetic muscimol on SNC and SNR neurones appears to be indicated from systemic administration studies. Thus, cells of the SNC increase their activity following muscimol, and this action was insensitive to picrotoxin (Waiters and Lakoski, 1978; McNeil et al., 1978). On the other hand, the activity of SNR neurones was depressed; this effect being reversed by bicuculline or picrotoxin (McNeil et al., 1978). There appears to be separate functional areas within the SNR itself, since unilateral microinjections of the neuronal GABAuptake inhibitor ACHC into rostral regions produces ipsiversive circling behavior and a reduced striatal DA turnover, while picrotoxin, biculline or tetanus toxin produced the opposite effects (Scheel-Kruger et al., 1977; James and Starr, 1978). These latter responses

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were abolished by cerebral peduncle lesions, 6-OHDA pretreatment and by systemic haloperidol. However, when ACHC or picrotoxin was injected into caudal areas of the SN, the circling behavior was opposite to that produced by rostral drug placements and was not accompanied by changes in striatal DA turnover or sensitive to haloperidol (Oberlander et al., 1977; James and Start, 1978, Straughan and James, 1978). It would therefore seem that there exists two SN systems, DA-ergic and non-DA-ergic, which may be influenced by GABA but exert opposite behaviors. Essentially similar conclusions have been reached following experiments with unilateral kainic acid lesions in the SNR. These, like electrolytic SNR lesions (Schwartz et al., 1976; Dray et al., 1977), produced chronic contraversive circling behavior which was unaffected by bilateral 6-OHDA lesions of the nigro-striatal DA system (DiChiara et al., 1977a). It may of course be possible that the nigral projections to the tectum or reticular formation mediate some aspects of non-DA-ergic behavior (e.g., see Section 6.2.2). Thus, nigral projections to the tectum have been suggested to interact with the tecto-spinal system regulating neck movements (York and Faber, 1977). Indeed, stimulation of the SNR no longer evoked contralateral head turning or body circling after lesions of the superior colliculus (York, 1973; Motamedi and York, 1978), though the motor asymmetries produced by 6-OHDA nigro-striatal lesions still remained after cortical or superior colliculus lesions (Crossman et al., 1977; Crossman and Sambrook, 1978). The non-DA-ergic pathway to the tectum may use GABA as a neurotransmitter though the additional involvement of a descending DA-ergic projection to this region has not been entirely excluded (Motamedi and York, 1978; Vincent et al., 1978). Complex adaptive changes also occur in SN DA-ergic activity following manipulations of GABA activity with agents having persistent actions. Thus, the long-lasting unilateral elevation of SN GABA produced by GABA-T inhibition increased nigro-striatal DAergic activity which resulted in a hyposensitivity of striatal DA-receptors (Oakley and Dray, 1978). Animals treated in this manner, however, showed little change in spontaneous behavior, though an imbalance of striatal DA-receptor function was revealed by the systemic administration of DA-ergic stimulants. In addition, striatal stimulation was less effective in inhibiting neuronal firing in the ipsilateral SN, possibly due to a desensitization of SN GABA receptors or to a reduced release of GABA from striato-nigral terminals (Oakley and Dray, 1978). Prolonged intranigral infusion of GABA also produced complex effects on nigro-striatal DA release, consisting of a brief increase in 3H-DA release followed by a decrease, and then by a more prolonged increase.(Cheramy et al., 1978a). On the other hand, chronic destruction of striato-nigral GABA fibers enhanced the behavioral effects of unilateral intranigral muscimol microinjections, and this appeared to be highly correlated with increased GABA-receptors in the SN, possibly reflecting a denervation supersensitivity phenomenon (Cross and Waddington, 1978). These pharmacological manipulations of the SN GABA system may, however, be misleading as far as determining the physiological relationship with the DA-ergic system and behavioral responses. For example, microinjections of GABA-mimetic drugs may produce different excitability changes when administered into different regions of the neuronal dendritic field (proximal DA dendrites and the long distal DA dendrites) or activate receptors on unmyelinated axons (e.g., striato-nigral or raphe-nigral fibers and terminals) (e.g. see Andersen et al., 1978; Brown and Marsh, 1978; Oakley and Dray 1978; Arbilla, et al, 1979; Gale, 1979). Such actions may depend on existing neuronal activity and may in fact be mediated through the altered release of other nigral transmitters. Thus, at present, caution should be exercised in attributing physiological significance to the pharmacological manipulations described following microinjections into the SN (see, e.g., Thiebot and Soubrie, 1979). 6.4.5. Glycine in substantia nigra Little attention has been paid to the possible function of this inhibitory amino-acid in the SN. Significant amounts of glycine occur in the SN (see Table 4) though its localization has not been determined. As in other brain regions, microetectrophoretic adminis-

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tration of glycine depresses neuronal activity in the SN by a strychnine-sensitive process (Crossman et al., 1974; Dray et al., 1976a; Dray and Straughan, 1976). Moreover, depolarizing stimuli released glycine from SN slices by a Ca 2 +-dependent process and this release may be blocked by tetanus toxin (Straughan and James, 1978; James and Starr, 1979a). It has been suggested that glycine-releasing interneurones may tonically inhibit nigro-striatal DA-ceUs (Dray et al., 1977). Confirming and extending this hypothesis, intranigral administration of glycine was shown to reduce 3H-DA release from the ipsilateral striatum. Strychnine also stimulated DA release but abolished the inhibitory effect of glycine (Cheramy et al., 1978b). Furthermore, unilateral microinjections of glycine produced weak ipsiversive turning behavior, whereas strychnine produced the opposite response (James and Starr, 1979a). On the other hand, Mendez et al. (1976) reported contraversive turning following the unilateral implantation of glycine crystals in the SN. 6.4.6. A C h in substantia nigra Significant amounts of ACh and ChAT activity are present in the SN (McGeer et al., 1973; Fonnum et al., 1974; Brownstein et al., 1975; Cheney et al., 1975; Jacobowitz and Goldberge, 1977; Vizi and Palkovits, 1978) together with cholinergic muscarinic receptors (Kobayashi et al., 1978). Also, calcium-dependent ACh release occurs from SN slices (Massey and James, 1978). Although histochemical staining for AChE suggested a striato-nigral cholingergic pathway (Olivier et al., 1970), transection of the striato-nigral pathway showed no significant depletion of ChAT in the SN (McGeer et al., 1971 ; Fonnum et al., 1974). Indeed, the strio- and pallido-nigral projections appear not to contain significant amounts of ACHE, and striatal AChE-containing neurones appear to be aspiny interneurones (Lehmann et al., 1979). Thus, the nigral cholinergic system would appear to be intrinsic. On the other hand, recent studies showed that SN ChAT activity was unchanged following kainic acid injections into the SN (Nagy et al., 1978c). This would imply that ChAT (and thus ACh) was not contained in SN neurones. Though it is possible that cholinergic neurones may be insensitive to the neurotoxic action of kainic acid it may also indicate that ChAT is contained in terminals of nigral afferent fibers. SN neurones, particularly those in the SNR, are sensitive to the local administration of ACh, being excited by the activation of muscarinic or nicotonic receptors (Aghajanian and Bunney, 1975; Dray et al., 1976a; Dray and Straughan, 1976; Roth and Bunney, 1976; Kemp et al., 1977). A small proportion of SN cells, may, however, be depressed by ACh (Kemp et al., 1977). Though the high AChE activity of the SN appears to be significant, this enzyme is considered to be a poor marker for cholinergic neurones (Fonnum et al., 1974). It is, however, particularly abundant in DA-containing neurones of the SNC and has been suggested to inactivate a cholinergic input into this region (Butcher and Hodge, 1976; Butcher and Bilezikjian, 1975). However, since only 40% of AChE activity remains after kainic acid lesions of the SN, and since 6.-OHDA lesions reduce its activity by 40%, it has been suggested that only 40% of nigral AChE is present in DA neurones, while 20yo is contained in other SN neurones and 40% in afferent SN terminals (Nagy et al., 1978c). Lesions of the SN have been reported to decrease AChE activity (Kim, 1973) (possibly due to destruction of DA neurones), but others suggest that it remains unchanged (Lynch et al., 1972; McGeer et al., 1971). One the other hand, nigral stimulation releases AChE into the CSF, while local administration of AChE depresses the activity of SNC neurones (Greenfield and Smith, 1976; Greenfield and Stein, 1978). Though the significance of these findings is not apparent it is possible that AChE may have a function in the SN or striatum other than that of ACh degradation. Though the microelectrophoretic studies discussed above suggest an excitatory function for ACh in the SN, microinjection studies with cholinergic agents suggest that these have a net inhibitory function on DA neurones. Thus, infusions of atropine into the SNR

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(which blocks endogenous cholinergic transmission) produced an increase in striatal 3H-DA release, while cholinomimetic agents decrease the release (Javoy et al., 1974). This inhibitory effect of cholinergic drugs on striatal DA turnover may be blocked by neuroleptics (James and Massey, 1978; Straughan and James, 1978). Additionally, microinjected hemicholinium (which blocks ACh synthesis) also increased striatal DA turnover (James and Massey, 1978). However, since cholinergic agents activated the release of DA from in vitro SN slice preparations (Straughan and James, 1978) it would appear that the in vivo effects of microinjected agents could be mediated indirectly. On the other hand, Wolfarth et al. (1974) have shown that the direct administration of cholinergic agents into the rabbit SN appeared to directly stimulate the nigro--striatal DA system, as judged from behavioral and electrographic signs. Clearly, these inconsistencies require explanation. 6.4.7. Substance P in substantia nigra Electrophysiologically, substance P has an excitatory function in the SN and may be the transmitter in the striato-nigral excitatory pathway (see Section 6.3.1.2). Unilateral focal injections of substance P into the SN produce behavioral effects compatible with an increase in nigro-striatal DA activity (Olpe and Koella, 1977b; James and Starr, 1977), though these effects may be weak (Huston and Staubli, 1978). Indeed, an increase in DA metabolites and 3H-DA release from the ipsilateral striatum followed the infusion of SP into the SN (Cheramy et al., 1977b; Cheramy et al., 1978c; Waldmeier et al., 1978), while SP also increased the uptake and release of 3H-DA in SN synaptosomal preparations iSilbergeld and Waiters, 1979). Thus, these findings suggest a direct activation of the DA system by the administration of SP. However, the actions of SP appear to depend on the precise localization of its injection ~vithin the SN. Thus, injections into the SNR produced brief contraversive circling accompanied by stereotyped behavior, and an increase in ipsilateral striatal DA-turnover. Conversely, injections localized to the SNC or lateral SN evoked ipsiversive circling and a fall in striatal DA turnover. The behavioral responses to SP injections were blocked by pretreatment with haloperidol and exaggerated by nialamide, suggesting their mediation though monoaminergic mechanisms (James and Starr, 1977, 1979b). 6.4.8. Enkephalin in the substantia nigra Small but significant amounts of the pentapeptide enkephalin are found in the SN (Hong et al., 1977a), and dorsolateral SN neurones exhibit enkephalin-immunoreactivity (Hokfelt et al., 1977), while enkephalin fibers have been observed in close proximity to SNC neurones (Johansson et al., 1978). Though the function of enkephalins within the SN has not been systematically explored, it is tempting to suggest that its release may be associated with activation of opiate receptors in the SN which are located predominantly on DA neurones of the SNC (Snyder, 1975; Pollard et al., 1978). Indeed, both systemic and microelectrophoretic morphine has been reported to increase the firing of SNC neurones, and this action is naloxone-sensitive (Iwatsubo and Clouet, 1977; J. Davies and A. Dray, unpublished). No studies regarding the effects of enkephalin on SN neurones are available. However, it may be of interest that neurones in the SN are activated by peripheral stimulation (Feger et al., 1978), and in particular may be activated or depressed by noxious peripheral stimuli (Barasi, 1979; Barasi and Pay, 1979). Whether such effects are mediated by enkephalin release is not known.

7. Functional Properties of Basal Ganglia Components Having discussed the variety of connnections between basal gangliar structures and other related brain regions it is of interest to examine the studies in which the functional properties of these areas have been explored. The thrust of such studies has been generally directed towards: (1) examining the behavior and motor consequences produced by

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lesions in basal ganglia, (2) correlating electrical activity, both gross neuronal and single cell, with discrete limb or body movements, and (3) examining the consequences of pharmacological and biochemical manipulations of neurotransmitters in discrete basal gangliar nuclei with respect to motor performance and electrophysiologicai activity. 7.1. LESIONSTUDIES Both clinicopathological observations and experiments on laboratory animals have been interpreted to indicate principally a motor function for the basal ganglia (DennyBrown, 1962; Martin, 1967; Laursen, 1963). For example, diseases that commonly affect the basal ganglia, e.g., Parkinsons disease, Huntington's chorea and Wilson's disease, show a general tendency to produce involuntary movements that progress slowly to states of maintenance of abnormal attitudes (see Marsden and Parkes, 19731. Acute destructive lesions, e.g., gas, heavy metal or drug intoxication, anoxia and isolated necrosis, by contrast, produce striking disorders of attitude much earlier. Clinical studies of basal gangliar damage, however, often show evidence of more-or-less diffuse involvement of several structures and thus for the elucidation of particular roles for individual structures experimentally induced, controlled lesions are more helpful. Though it is possible to produce little change in motor behavior after unilateral or bilateral lesions in the caudate-putamen or globus pallidus (Ranson and Berry, 1941; Kennard, 1944; Denny-Brown, 1962; Laursen, 1963), Denny-Brown (1962) describes hyperkinesa in monkeys (in the presence of other monkeys) following large bilateral caudate lesions with little change in reflexes or loss of visual or tactile placing. Lesions in the putamen produced soft, yielding rigidity without consistent abnormality of posture. Pallidal lesions (including the ansa lenticularis and frontopontine tract) were more striking, producing a loss of placing and righting reflexes, followed by slow but incomplete recovery of some functions, e.g., ambulation and righting (Denny-Brown, 1962). Since only with large lesions (often those damaging adjacent structures) was significant motor impairment produced, Denny-Brown suggests that the physiological function of these structures is of a relatively uniform kind. Thus, small lesions allow the remaining structures to compensate for the degree of loss. In fact, lesions of the subthalamic nucleus (particularly unilateral) produce consistent dyskinesia, hemiballism and hemichorea of the contralateral extremities when at least 20~o of the structure is damaged (Carpenter et al., 1950; Whittier and Mettler, 1949b; Martin, 1960; Pentshaw et al., 1963). Apparently the pallidus and lenticular fasciculus are necessary for the expression of these STN effects (Carpenter et al., 1950). In a series of experiments involving large caudate lesions or complete bilateral removal of the caudate in cats, Villablanca et al. (1976) describe a long lasting "compulsory approach syndrome". This was characterized by stereotyped and prolonged approaching or following of persons, objects or other cats. Other components of the syndrome were marked passivity, exaggerated forelimb treading, purring, rooting, hyperactivity and reactivity. Bilaterally acaudate cats were, however, remarkably free o f permanent gross neurological deficits. Deficits such as. motor weakness, awareness, defective eating and drinking were only observed in the early postoperative period. Also, in unilaterally acaudate animals there was an absence of permanent gross neurological and behavioral changes. These authors concluded that the caudate nuclei appear not to have essential roles in basic metabolic function, elementary sensory-motor function, or elementary cognitive processes. Regarding this latter suggestion, caudate lesions in infant primates produce consistent "cognitive" deficits, e.g. in performing delayed response tasks involving mnemonic abilities (Kling and Tucker, 1967), while prenatal damage in humans may produce mental retardation (Tobin, 1969). Additionally, bilateral or unilateral destruction of the substantia nigra, particularly the SNC in infant rats resulted in transient cessation of suckling, drinking and feeding, as well as dysfunctions in a variety of sensorimotor behaviors. However, recovery of all these functions eventually occurred, though residual regulatory

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defects in feeding and drinking in male rats seemed permanent (Almli and Fisher, 1977). On the other hand, unilateral lesions of the striatum or entopeduncular nucleus in lower animals have been shown to produce ipsiversive turning or circling behavior (Dankova, et al., 1975; Anden et al., 1966a). Another approach has been to test the ability of animals to perform learned movements during reversible cooling of basal gangliar structures. In the experiments described by Hore et al. (1977), monkeys were trained to move a handle in a horizontal arc of about 60 ° between two targets by making alternate flexion and extension movements at the elbow (Fig. 36). Since the animal's view of the target was blocked by an opaque screen, flexion and extension targets were indicaged by lights that lit when the handle was on target. This provided proprioceptive cues for the position of the targets. The monkeys usually made smoothly executed rhythmic movements between targets. However, during restricted cooling of the contralateral globus pallidus by means of a cryoprobe, which produced a temporary functional lesion, this pattern disintegrated and movement became jerky, smaller in amplitude, and irregular (Fig. 36). When the monkey was able to see both target and handle position, however, all tasks were successfully performed despite G P cooling, though there was still some motor impairment. These observations may offer some explanation why signs of motor deficits are not always Seen after lesion experiments, since visual guidance probably enables the animal to compensate to some degree for conscious motor deficiencies. Similar experiments by Caan and Stein (1979) suggest that unilateral globus pallidus cooling produces relatively little im-

1 M~L 8 ~fil 75

M33L 8 ~ FIG. 36. Impairment of self-paced nonballistic elbow movements, performed without visual guidance during GP cooling (7-10°C). Upper left shows the experimental situation with the monkey's arm on the movable handle. The animals view of its arm is blocked by an opaque plate (dashed

line). Records show the handle position as four monkeys made alternating movements between mechanically undetectable flexion(F) and extension (X) targets. Impaired movements were seen within minutes after the start of cooling the GP, and normal movements returned again within minutes after cooling was stopped. To the left are drawings of frontal sections showing the position of the implanted cooling sheaths for each animal. The dashed lines show the estimated 18°C isotherm when the sheath thermocouple reads 10°C. GP, globus pallidus; P, putamen; C, caudate: IC, internal capsule; AC, anterior commissure; OT, optic tract; A, amygdala. (From Hore et al., 1977; reproduced with permission.)

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pairment of slow movements of the contralateral arm in pursuit of slowly-moving visual targets, but rapid extensor movements were badly impaired. Cooling to a temperature just above freezing prevented animals from making any movements with the contralateral arm at all; the limb appeared frozen in flexion. These experiments thus suggest that the globus pallidus may have a role in processing proprioceptive information and functions in the central programming of movement, particularly ballistic programmes, which cannot be controlled by continuous feedback (see also the single neurone studies). Lesions of the GP also produce changes in complex behavioral patterns which are unrelated to motor disabilities. For example, gothic-type male squirrel monkeys perform a highly predictable variation of a naturally occurring display shown in aggression, in courtship and in greeting when placed in front of a mirror. Vocalization, thigh-spreading and forward thrusts of the erect phallus are the major and most regular occurring signs (MacLean, 1978). Lesions, particularly in the GPI, produce a long-term elimination or fragmentation of this behavior. Pallidal projections to the VA appear to be particularly involved. Since lesions in other areas were unable to reproduce this deficit, MacLean (1978) suggests that the pallidus may play a basic role in the organized expression of species-typical behavior. Unilateral and bilateral electrolyic lesion of the SN produce a number of complex behavioral changes and sensory deficits, which have been attributed to rather specific damage of the nigro-striatal DA pathway (e.g. Ungerstedt, 1971b; see Section 7.4.1). Amongst the behavioral effects are hypoactivity, adipsia and aphagia following bilateral destruction, while unilateral damage causes spontaneous circling or turning behavior (see Section 7.4.1 for comprehensive description). Such lesions of the SN have been made in an attempt to reproduce the spectrum of motor deficits observed in PD in which lesions of the SN present a common histopathological finding. It seems, however, that focal SN lesions in laboratory animals do not readily replicate the symptoms of PD. For example, it appears that besides the SN, additional lesions in the rubro-olivo-cerebello-rubral loop are required to produce tremorgenic activity resembling that in PD (see Poirier, 1974; Poirier et al., 1975). Moreover, tremorgenic activity is probably generated by a thalamo-cortical system (see Lamarre, 1975), which may be influenced through the VA-VL thalamus by inputs from the cerebellar nuclei, strio-pallidal system and SN. Indeed, thalamic relay neurones fire in synchrony with the contralateral limb tremor of PD patients (Albe-Fessard et al., 1966; Jasper and Bertrand, 1966) and lesions in this area (VL-VA) reduce tremor movements in the contralateral extremities. Additionally, Poirier (1974) suggests that although both the akinesia and rigidity of PD involve a common defect in nigro-striatal DA mechanisms, they depend on associated disturbances in other areas of the CNS. 7.2. STIMULATIONSTUDIES

Stimulation of the striatum produces many apparently unrelated phenomena. For example, it inhibits neurones in the cerebral cortex (Spehlmann et al,, 1960; Liles and Davis, 1969), but excites other cells, e.g., in the inferior olive (Sedgwick and Williams, 1967). Spinal reflexes, afferent discharges of flexors or extensors and activity in gamma motoneurones may be enhanced or depressed, depending on the localization of the stimulus site and the level of anesthesia employed (Stern and Ward, 1962; Liles and Davis, 1969; Granit and Kaada, 1953; Bruggencate, 1975a, b). Facilitating effects on spinal-cord activity have been suggested to be mediated by caudate influences on GP neurons, which in turn alter the activity of pyramidal tract neurones as well as the outputs of other subeortical structures (Newton and Price, 1975). However, caudate stimulation also has an inhibitory effect on somatic afferent transmission in the cuneate nucleus which is independent of cortical influences (Jabbur et al., 1976) and suggests a role for t h e caudate in sensory integration. It is possible that the effects on spinal transmission could be mediated via the SN. Stimulation of this structure increases reflex responses in both flexor and extensor motoneurone pools independently of cortico-

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spinal influences, and might be relayed via a reticulo-spinal tract involving DA-ergic transmission (York, 1972b; Hassler and Wagner, 1975; Anden et al., 1971) (see Section 6.2.2). Behavioral observations also show that stimulation of basal ganglia produces a variety of effects. For example, unilateral stimulation of the caudate nucleus in alert animals evokes contraversive head turning and circling or flexion of contralateral extremities combined with contraversive head turning (Buchwald and Ervin, 1957; White and Himwich, 1957; Stevens et al., 1961; Laursen, 1963; Barnett and Goldstein, 1975). Similar effects are produced by pallidal and entopeduncular stimulation (Hassler and Dieckmann, 1968). On the other hand, inhibitory reactions are also observed during striatal stimulation. Thus, caudate or pallidal stimulation inhibits movements evoked by cerebral cortical stimulation, while low-frequency caudate stimulation produces inhibition of ongoing instrumental behavior and a state of quiescence resembling catatonia and sleep (Hodes et al., 1951; Buchwald and Ervin, 1957; Jung and Hassler, 1960; Akert and Anderson, 1951; Buchwald et al., 1961c; Deadwyler et al., 1974; Shapovalova, 1978). Both types of inhibitory effect have been suggested to be relatively unspecific, in that inhibition of cortically evoked movement was considered to be due to stimulus spread, particularly to the internal capsule (see, e.g., Laursen, 1963), while sleep-like states occurred only after a long latency, and were also induced by stimulation of several other brain areas (Laursen, 1963). Behavioral changes upon stimulation of the striatum or pallidum are in fact best seen when conditioning procedures are used. Thus, e.g., stimulation of the striatum may interfere with acquisition of a visual discrimination task and prolong the response time of a task already learned (Buchwald et al., 1961b). Many workers have shown that electrical stimulation of the caudate can evoke a typical electrophysiological response. This response (usually to a single shock stimulus) consists of a high-voltage rhythmic oscillation termed "caudate spindles" (Buchwald et al., 1961; Goldring et al., 1963; Kitsikis et al., 1968; Laursen, 1963), which also initiates rhythmic activity in the diffuse thalamic projection system and cerebral cortex and suggests that the caudate is involved in functional control of "alertness", attention and wakefulness (e.g., see Buchwaid et ai., 1961d; Buchwald et al., 1961a; Heuser et al., 1961). The initiation of caudate spindle activity by electrical stimulation or drugs, e.g., cholinomimetics, is suggested to mediate some of the concomitant behavior changes described above (see Buchwald and Hull, 1967; Poussart and Langlois, 1976). Electrical stimulation of the SN also produces motor responses consisting of contraversive circling and stereotyped behavior, e.g., licking, sniffing and gnawing. This is considered to result from activation of the nigro-striatal DA system (Arbuthnott and Crow, 1971; Arbuthnott and Ungerstedt, 1975; see Section 6.2.2). In addition, lowintensity SN stimulation produces disruption of learned behavioral tasks (Routtenberg and Holzman, 1973), suggesting that such stimulation interferes with the neurochemical and neurophysiological events in the striatum which are important substrates for longterm memory (Fibiger and Phillips, 1976; Gold and King, 1972; Wyers et al., 1973). Though both the lesion experiments and those involving stimulation of basal ganglia indicate the complexity of processes occurring in these structures, they merely suggest their involvement in motor, cognitive and elaborate behavioral processes, but do not offer explanations for individual nuclear roles. Perhaps the single-cell studies to be discussed below begin to offer some coherent insight into the way in which components of the basal ganglia might function. 7.3. CORRELATIONS OF MOTOR PERFORMANCE AND SINGLE-CELL ACTIVITY While numerous studies have been devoted to investigating the properties of single neurones in the basal ganglia in anesthetized or otherwise immobilized animals, few have explored their properties in freely moving, awake animals. Using techniques for extracellular single-cell recording from freely moving animals developed by Evarts (1966, 1968), Travis and others (Travis et al., 1968; Travis and Sparks, 1967, t968) found, in the

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squirrel monkey, that a small percentage of neurones in the globus pallidus discharged in relation to limb movements. Many other cells, both in the putamen and pallidus, discharged in relation to food acquisition or consumption and also during visual attention (Buser et al., 1974; Sparks and Travis, 1973; Kitsikis et al., 1971). Cells in both the monkey, cat and rat caudate and globus pallidus also showed changes in activity related to all phases of performance of a complex task incorporating attention to a visual stimulus, response inhibition, phasic limb flexion and consumption of juice reward (Soltysik et al., 1975; Lidsky et al., 1975; Dolbakyan et al., 1977). The conclusions reached from these studies was that the pallidum had an important role in feeding behavior, acting to control other motor systems which were involved in securing and consuming food. Subsequent studies by DeLong (1971, 1972) indicated that neurones whose activity correlated with feeding behavior were those on the border of the globus pallidus lying within the substantia innominata. On the other hand, the firing of pallidal neurones (both in GPE and GPI) in response to consummatory activity was considered to be related to the sensory rather than motor aspects of ingestion (Lidsky et ai., 1975; Neafsy et al., 1978a). Thus, although pallidal and entopeduncular neurones appear to be concerned both with movement and consumptive behavior, the precise significance of this is unclear. In fact, these sensory responses appear to be unrelated to the motivational or rewarding properties of the stimulus, but were considered to be more closely related to afferent mechanisms involved in the control of the oropharyangeal musculature (Lidsky et al., 1975). Neurones in the putamen, caudate and globus pallidus also display typical discharge patterns when the animal sits quietly. Thus, caudate and putamen cells have slow discharge rates (< 10/sec), whereas those in both pallidal segments discharge at higher rates (DeLong, 1971, 1972; Buser et al., 1974; DeLong and Strick, 1974; Anderson, 1977). In particular, neurones in the GPI discharge continuously without long intervals of silence but with brief fluctuations in rate. On the other hand, GPE neurones show two distinct patterns:those with recurring high-frequency bursts with long intervals of silence (857~o of cells), and others with low-frequency discharges with short bursts (15~). Both types of cell appear to be randomly intermingled throughout the GPE. When monkeys, with mechanical stabilization of the head, made natural, self-initiated or visually-cued alternating arm or leg movements, some neurones in the putamen and in both segments of the globus pallidus showed changes in discharge that were temporally related to the movements (see Fig. 37). Although the discharges of pallidal neurones and ipsilateral limb movement alone showed little relationship, those to contralateral limb movements were very closely related (DeLong, 1971, 1972, 1973) (Fig. 38). In very few

I

I lOOmsec

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FIG. 38. Activity of a high-frequency discharging unit in the external pallidal segment with a monkey resting (A), during push-pull (B), and side-to-side (C) movements of the contralateral arm, and during push-pull (D) and side-to-side (E) movements of the ipsilateral arm. The line below the action potential records represents the position of the movable rod. For push-pull movements, up is for pull and down for push; for side-to-side movements, up is for extension and down is for flexion. The discharge pattern of this cell is phasically related to both push-pull and side-to-side movements of the contralateral but not of the ipsilateral arm. The firing pattern is different for the push-pull and side-to-side movements of the contralateral arm. (From DeLong, 1971 : reproduced with permission.)

cells, however, was activity related to changes in both contralateral arm and leg movements. Moreover, there appeared to be an anatomically distinct distribution of neurones whose discharge pattern was related to contralateral arm or leg movement. There also appeared to be differences in the anatomical distribution of neurones which responded during limb movements at different speeds. Thus, DeLong and Strick (1974) concluded that the discharge of a large proportion of neurones in the putamen was preferentially correlated with a slow, ramp-like movement between two targets, as opposed to rapid, ballistic movements between two mechanical stops (Fig. 39). Only a few movementrelated pallidal neurones showed a preferential correlation with slow movements, the majority being active during ballistic movements (DeLong, 1971, 1972). In a different experimental paradigm, Anderson (1977) has shown that neurones in all portions of the monkey putamen and globus pallidus (particularly the GPE) change their discharge rate when active postural adjustments, necessary to maintain a restricted head position, are made during static or dynamic tilting of the chair in which the animal sits. Although numerous sensory inputs from cutaneous, muscle, joint, vestibular, auditory or visual receptors could have influenced the firing pattern of basal gangliar neurones, firing patterns were only changed during activity-initiated postural adjustments. No changes were in fact observed to passive manipulation of limbs, the head, or to visual stimulation or electrical stimulation of vestibular structures (see also Buser et al., 1974). Such studies in primates also reveal that discharges of basal gangliar neurones sometimes precede the occurrence of movement (DeLong, 1971, 1972), events which have been consistently observed in the motor cortex (e.g., Evarts, 1966; Neafsey et al., 1978b) or cerebellum (Thach, 1970a, b). Thus, the hypothesis that the basal ganglia have a role in preparation for and initiation of movement has recently been supported by similar studies in cats. Neafsey et al. (1978a) showed that in cats trained to depress a bar with their forepaw for a food reward (this involved a forelimb flexion movement), neuronal firing both in the GP and in the entopeduncular nucleus correlated with the limb movement. Some cells, however (40%), increased their discharge rate some 500 msec or more

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FIG. 40. Example of an early firing entopeduncular neurone in the cat. Cats were trained to depress a bar with their forepaw for a minimum of 2 sec. When the bar was released the cat received a food reward. The movement thus required the performance of a forelimb flexion. The top trace indicates the bar position and the point at which it is released, BR. The middle trace shows that the activity of the recorded neurone increases some time before the forelimb flexion movement. The bottom histogram (an averaged 10 trials) shows the summed activity of this cell (M = mean activity of the first 10 bius) and the shaded black bins are more than 2 S.Ds above or below M. The onset of increased cell activity is some 20 bins (1000msec) before the bar is released. (From Neafsey et al., 1978a; reproduced with permission.)

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before movement began (Fig. 40). Moreover, movement-related neurones have been found in the VL-VA thalamus, some of which also fire before the initiation of movement (Strick, 1976; Neafsey et al., 1978a). These single-cell experiments in freely moving animals have particular significance in formulating a hypothesis regarding basal gangliar function. For example, Kornhuber (1971) has suggested, on the basis of clinical and experimental findings, that the basal ganglia function primarily in the generation of slow, ramp movements, whereas the cerebellum functions largely in the preprogramming and initiation of rapid, ballistic movements. Rapid, saccadic or ballistic movements must be entirely preprogrammed, since there is inadequate time for modification of the movement by peripheral sensory feedback during brief displacements. Slow movements, however, may be modified during the course of movement on the basis of peripheral sensory feedback (see also Evarts, 1971; Kornhuber, 1974; Bruggencate, 1975a). Both the experimental observations of DeLong and Strick and clinical observations support this hypothesis to a great extent. For example, the rigidity and akinesia in PD point to a deficit in smooth movement generation, whereas ballistic eye movement is not significantly impaired (Butz et al., 1970). Particular significance has also been attached to the early firing of basal ganglia neurones preceding the initiation of movement. This has been suggested to be the neuronal correlate of the state of "response set" which exists as preparatory adjustment for performing motor tasks (Neafsey et al., 1978a; Buchwald et al., 1975; Soltysik et al., 1975). The "response set" is concerned with priming or tuning the neuronal mechanisms concerned with integrated movements of the body and limb, as opposed to those neuronal mechanisms concerned with discrete movements of distal musculatures (Lawrence and Kuypers, 1968; Neafsey, et al., 1978a). Thus, "the basal ganglia are not importantly involved in producing discrete movements per se, but rather their role lies in the relatively long-term biasing of firing thresholds of groups of neurones closer to the final common path. As a result of this bias, the probability that these latter neurones will respond to inputs coming from elsewhere in the brain is altered" (Buchwald et al., 1975). Thus, damage in the basal ganglia, e.g., in PD producing symptoms of hypokinesia and difficulty in initiating voluntary movement may result from malfunctioning of the "response set" system. 7.4. FUNCTIONALLY RELATED CHANGES BY NEUROTRANSM1TTER MANIPULATIONS IN BASAL GANGLIA

Experimental manipulations of neurotransmitters in basal ganglia by means of pharmacological agents or selective neurotoxins have been made to explore the role of specific neuronal pathways or individual transmitters in mediating certain aspects of behavior and motor function of these areas. Additionally, such manipulations have been used to provide experimental animal models for analysing human disease states such as PD, HD and, e.g., the tardive dyskinesia syndrome of chronic neuroleptic therapy. 7.4.1. Chemical lesion studies As outlined earlier (see Section 7.1), attempts to reproduce the symptoms of PD by discrete brain lesions has not been entirely successful. However, rodents show easily quantifiable behavioral changes when the nigro-striatal DA-ergic system is damaged by injections of the neurotoxin 6-OHDA in an attempt to replicate the DA deficiency of PD. Though there has been some debate about nonspecific neuronal damage produced by localized injections of this agent (e.g. see Butcher et al., 1974; Poirier et al., 1972; Maler et al., 1973), bilateral nigro-striatal lesions produce changes in motor activity e.g., akinesia, and also adipsia and aphasia whose intensity appears to be highly correlated with the degree of striatal DA loss and the number of damaged DA neurones in the SN (Ungerstedt, 1971b; Ranje and Ungerstedt, 1977). On the other hand, unilateral lesions of the nigro-striatal DA-ergic projection or striatal DA terminals tend to produce ipsiver-

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sive head deviations (torticollis in monkeys) or to make animals spontaneously circle towards the lesioned side (Ungerstedt, 1971b; Crossman and Sambrook, 1978b). This tendency to ipsiversive circling activity may be changed to continuous rotational behavior when DA-release is increased in the remaining undamaged striatum by injections of amphetamine (e.g. Ungerstedt, 1971b; Costall et al., 1976a). Conversely, administration of apomorphine causes these animals to circle away from the lesioned side by preferential stimulation of DA receptors in the ipsilateral striatum that have become hypersensitive following DA-denervation. In addition, there DA-receptor stimulating drugs produce stereotyped behavior patterns, e.g. persistent sniffing licking and gnawing (see Ungerstedt, 1971b; lversen, 1977). The behavior changes produced by DA-receptor stimulants can be blocked by neuroleptic drugs. Unilateral DA-ergic lesions also produce temporarily impaired orientation to visual, olfactory and auditory stimuli presented to the contralateral side of the animal. However, additional impaired orientation to tactile stimuli appears to be permanent (Ungerstedt et al., 1977; Ljungberg and Ungerstedt, 1976). Siegfried and Bures (1979) recently suggested, however, that this sensory neglect was not due to sensory or motor failure, but rather to a reduced arousing efficiency of unconditioned stimuli and interference with sensorimotor integration. Indeed the sensory neglect may be compensated by conditioning procedures which indicate that the nigro-striatal system can be partly substituted by other neuronal circuits. Dopaminergic stimulant drugs also produce rotational behavior in normal animals. This is considered to be due to an imbalance in the functional activity of the nigrostriatal pathway on either side of the brain and is revealed by differential content of DA in the left and right striata and by differences in sensitivity of striatal DA receptors (Jerussi et al., 1977; Glick et al,, 1976; Thiebot and Soubrie, 1979). A number of mechanisms, in addition to activation of nigro-striatal DA pathways may cause rotational behavior in rodents (e.g., see Glick et al., 1976). For example, the descending nigro-reticular and nigro-collicular pathways (see Section 6.2.2) have recently been implicated in head turning and rotational behavior (York and Faber, 1977; Motamdei and York, 1978). Thus, although the nigro-striatal lesioned animals provide a useful model for studying striatal DA mechanisms, the neurophysiological mechanisms responsible for the behavioral consequences of such lesions are as yet not entirely understood. Recent biochemical studies suggest that intrastriatal injections of the neurotoxin kainic acid (a rigid analogue of the central excitant glutamic acid) (Olney, 1978) produces an animal model of HD (see Section 2). This agent produces generalized damage of cell bodies and dendrites without affecting axons (but see Mason and Fibiger, 1979) or afferent terminals, and this results in a neurological, cytological and neurochemical profile essentially similar to that seen in HD (Coyle and Schwarcz, 1976; McGeer and MeGeer, 1976b; MeGeer et al., 1978; Coyle et al., 1978). Moreover, this model has suggested the involvement of glutamate mechanisms in the etiology of HD (Olney and deGubareff, 1978b). Neuronal losses following kainic acid injections into the striatum are usually more complete than those typically seen in HD and are followed by gliosis, a feature not observed in HD (Lange et al., 1976). Behaviorally, intrastriatal kainic acid produces hyperactivity (Divac et al., 1978; Fibiger, 1978), especially during the animal's waking period. Similarly the choreiform movement in HD patients abates during rest and is absent during sleep (Duvoisin, 1972). Also, such animals show enhanced locomotor and stereotyped responses to amphetamine (Mason and Fibiger, 1978; Fibiger, 1978) similar to the exaggerated motor responses observed after such drug administration in HD patients (Klawans et al., 1972). Finally, kainic-acid-lesioned animals exhibit specific learning and memory deficits which may be related to defects in the cognitive function of the striatum and involve cortico-striatal mechanisms (Divac, 1972; Divac et al., 1978; Fibiger, 1978; Sandberg et al., 1978). In this regard, HD is almost always associated with progressive intellectual deterioration; including impairment of learning, memory and judgment (Garron, 1973; Sishta et a!., 1974; Slaby grid Wyatt, 1974). Thus, the "kainic acid model" appears to be particul~ly J.P.N. 14/4--F

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valuable in providing a means of elucidating the etiology of HD. Moreover, it also provides a potential model for obtaining electrophysiological data concerning both the short- and long-term consequences of neuronal degeneration in basal ganglia. 7.4.2. lntracerebral injection studies In keeping with the hypothesis that rotational behavior in rodents is due to an imbalance in the striatal DA activity of the two sides of the brain, direct unilateral injections of DA or DA-ergic agents into the striatum produces contralateral turning, especially if DA metabolism is inhibited (Ungerstedt et al., 1969; McKenzie et al., 1972). A similar effect is produced by DA in cats, including reduction of locomotor activity, contralateral head turning, choreo-athetosis of the contralateral forelimb, and mimicks the effects of low-frequency electrical stimulation of the caudate; both types of stimuli being blocked by neuroleptics (Cools, 1973). On the other hand electrically-induced head turning in rats may be antagonized by intracaudate injections of DA (e.g., Malick and Go!dstein, 1976). Difficulties in interpreting the functional role of striatal DA in behavioral tests are presented by the identification of two functionally-distinct DA sensitive sites in the cat. An ex.citation-mediating type, which is stimulated by DA and apomorphine and inhibited by haloperidol, appears to be localized on presynaptic terminals of non-DA-ergic neurones in the rostro-medial parts of the caudate. Their activation produces contralateral head movements and turning. There are also inhibition-mediating DA sites which are located diffusely around the rostro-medial caudate area on postsynaptic neurones innervated by nigro-striatal DA terminals. Their activation produces ipsilateral head turning. The inhibition-mediating sites may be inhibited by ergometrine and noradrenaline, but are unaffected by apomorphine or haloperidol (e.g., see Cools and Janssen, 1976; Cools and Van Rossum, 1976). Similar studies using intracerebral injections of GABA also suggest an important function in the striatum, especially regarding an interrelationship with DA-mediated effects. Thus, GABA blocks contraversive head turning produced by electrical stimulation or DA-ergic drug injections in the striatum (Malick and Goldstein, 1976; Cools and Janssen, 1976). However, injections of GABA into regions where DA-agonists produce ipsilateral head turning results in similar effects as those produced by DA (Cools and Janssen, 1976). Clearly, the interactions of GABA with DA-ergic mechanisms, studied by means of intracerebral injection techniques, are complex, and like the interactions observed from in vitro neurochemical release studies (see Section 3.4) are subject to interpretive difficulties regarding functional roles for the neurotransmitters. Unilateral blockade of striatal GABA receptors with picrotoxin, however, produces contralateral myoclonic jerks which are independent of striatal DA or 5HT mechanisms (Tarsy et al., 1978). Moreover, intrastriatal curare also produces choreiform activity which seems to be independent of cholinergic mechanisms, since other antinicotinic agents do not produce similar effects (McKenzie et al., 1972). Possibly, the effects of curare, like those of picrotoxin, are due to antagonism of striatal GABA mechanisms (see e.g., Hill et al., 1973). Others have manipulated basal ganglia GABA activity by intracerebral injections of inhibitors of GABA metabolism. For example, bilateral injections of EOS (an irreversible inhibitor of GABA-T) into the globus pallidus results in profound akinesia, which correlates with the elevated GABA concentration. This effect can be partially reversed by similar administration of picrotoxin, which in turn produces mild arousal at small doses and myoclonic jerks of trunk and hindlimbs in higher doses (Pycock et al., 1976). Intrastriatal injections of cholinergic agents or inhibitors of AChE generally appear to produce few behavioral signs (McKenzie et al., 1972). Others report ipsiversive turning behavior and enhancement of contralateral turning evoked by intrastriatal haloperidol injections (McKenzie et al., 1972; Costall et al., 1972) followed by periods of behavioral quiescence resembling that of low-frequency electrical stimulation of the striatum (Stevens et al., 1961). Tremorigenic behavior also results from activation of striatal

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cholinergic "muscarinic" receptors (Connor et al., 1966; Mathews and Chiou, 1979) and may be related to the caudate spindle activity (Pousart and Langlois, 1976; see also Section 7.2). Apparently the effects of cholinomimetics are dose related. Thus, small doses of carbachol produce inhibition of ongoing learned activities, though animals remain alert and responsive to sensory stimuli. Larger doses produce a "rage" reaction (Hull et al., 1967). There are, however, several difficulties inherent in these intracerebral injection studies of the functional effects of putative neurotransmitters, since any hypothesis depends on specific assumptions concerning the locus and mechanism of action of such substances. Firstly, therefore, adequate precautions must be taken to limit the spread of injected materials, as this may be extensive (Bondareff et al., 1970; Grossman and Stumpf, 1969; Hull et al., 1967). Also, it is apparent that the behavioral effects produced by injected agents (which are assumed to have relatively specific effects) may not mimic any physiological synaptic activity, but rather be exerted on various membrane receptors which normally have no access to these agents. Thus, such manipulations may be useful in providing pharmacological "models" for drug evaluation, but provide little insight into the understanding of physiological processes. Finally, it is certain that behavioral effects are mediated by multisynaptic processes, many of which have yet to be identified physiologically or anatomically. Thus, conclusions regarding transmitter function in specific basal gangliar regions must remain extremely tentative. 7.4.3. Tardive dyskinesia It is well established that chronic intoxication with neuroleptic drugs induces Parkinson-like disorders in man, accompanied by late dyskinesias, akathesia and subjective sensory disorders (Ayd, 1961; Delay and Deniker, 1968; Tarsy and Baldessarini, 1976, 1977; Klawans, 1973). The tardive dyskinesia syndrome has been postulated to result from a functional excess of synaptic striatal DA activity produced by chronic neuroleptic blockade of DAtransmission and the induction of supersensitivity of DA receptors (Klawans, 1973; Tarsy and Baldessarini, 1973, 1974). The symptoms may be ameliorated by reinstating neuroleptic therapy. Though striatal cholinergic mechanisms have also been implicated treatment with cholinergic agents usually worsens the symptoms (Tarsy and Baldessarini, 1976). Essentially, the etiology of tardive dyskinesia remains unknown, though the prolonged course of the syndrome suggests that some permanent degeneration of neurones may occur. Attempts to replicate tardive dyskinesia in experimental animals have generally been disappointing. Only monkeys and baboons show neuroleptic-induced extrapyramidal features like those in man; most other laboratory animals show catalepsy (Dreyfuss et al., 1972; Sassin, 1975; Klawans and Rubovits, 1972b; Weiss and Santelli, 1978). Symptoms such as buccolingual dyskinesias, biting behavior, peculiar posture, writhing and stretching occur after several months of neuroleptic administration (Deaneau and Crane, 1969; Paulson, 1972; Weiss and Santelli, 1978). Although dyskinesias produced in several studies have not been long lasting, a recent study in New World primates (Weiss and Santelli, 1978) showed enduring sensitivity to haloperidol some 18 months after its discontinuation. Thus, a single administration after this period triggered a dyskinetic episode as intense as that requiring 6 months of chronic drug treatment to induce. This animal model thus provides a means of studying the etiology of drug-induced dyskinesias and presents experimental evidence for a not widely recognized therapeutic problem, that of long-term sensitivity to a class of drug after prolonged withdrawal. 8. Conclusions

It is evident from the foregoing discussions that there remain many unresolved questions concerning all the aspects of basal ganglia functions. The novel anatomical tech-

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niques have underlined the complexity of connections between basal gangliar components and other parts of the CNS. Many of these connections need to be further investigated using electrophysiological, pharmacological and biochemical methods. In particular, the significance of the elaborate mosaic arrangements of dendrites and cell clusters in the striatum as well as the nuclear subdivisions of the substantia nigra need to be explained. Do they in fact represent functionally related pockets of synaptic contacts, and how does the activity of their output neurones relate to discrete facets of behavior? In fact, greater attention should be directed towards exploring the significance of the topographical arrangements of efferent and afferent pathways of the basal ganglia. For example, the recording and stimulation of related sites in electrophysiological studies; the systematic microstimulation of functional sites in behavioral experiments; and the precise localization of injected agents and lesions in micropharmacological studies. Finally, we need more information on all aspects of the STN, and on the significance and extent of branched connections of basal ganglia neurones, e.g., SN neurones, projecting both to the superior colliculus and the thalamus. It goes without saying that despite the technical difficulties, the biophysical properties of basal gangliar neurones should be explored. Though some information of this nature is available, mainly from striatal neurones, it is still essential to compare the membrane excitability changes produced by synaptic transmitter release with those of locallyadministered candidates if the true identity of neurotransmitter pathways is to be revealed. Such studies, plus the judicious use of more selective pharmacological antagonists might, e.g., finally resolve the role of DA as one of the transmitters in the nigrostriatal pathway, and also confirm the identity of substance P as the striato-nigral excitatory transmitter. Of course, the widespread occurrence of receptors, e.g., DA and GABA, on presynaptic terminals, glia and on unmyelinated axons suggests the need for caution in the interpretation of pharmacological studies. These sites may, however, be of importance in considering the mechanism of action of therapeutic agents. It would seem that we are now nearer to defining some coherent role for the basal ganglia in brain function. Though the results of lesion studies have eluded precise explanations, they have suggested that a certain degree of compensatory activity may occur following basal ganglia damage. Experiments in freely-moving animals involving basal ganglia cooling or studying behaviorally-related changes in single-cell firing have been more rewarding. Thus, the basal ganglia appear to function in the central programming of movement, particularly the initiation and sequencing of complex behavioral patterns and motor tasks. Such functions would be modulated by motivational influences, and indeed circuitry from limbic structures to the basal ganglia is available. However, we also need to know to what extent the basal ganglia control the excitability of the thalamus or more direct supraspinal pathways, and how the thalamic nuclei integrate the diversity of information received from the basal ganglia and other motor circuits. Experimental studies of neurological diseases have also provided some insight into their etiology and their therapeutic management. For example, receptor binding data suggest that the ineffectiveness of cholinergic drug therapy in HD is due to loss of cholinergic receptors, while the changes in DA receptors during L-DOPA therapy of PD might explain the frequently encountered "on-off" symptoms. Also, experimental lesions of the striatum with kainic acid suggest a deficiency of glutamatergic neurotransmission in HD. On the other hand, the implantation of DA-containing neurones into the fetal rat striatum has been shown to reduce the motor abnormalities caused by striatal DAdeficiency (Perlow et al., 1979). Thus, it may be possible to use autografts or homografts of peripheral catecholamine-containing tissues in the future treatment of PD where the loss of nerve tissue function can be diagnosed to be reasonably well circumscribed. Finally, the dysfunction of polypeptide-containing pathways in basal ganglia disease suggests the need to pursue the development of other types of replacement therapy, as well as the need to elucidate the significance of peptidergic neurotransmission in the CNS.

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Acknowledgements I w o u l d like to t h a n k Ms Olivia Scott for typing the bulk of this m a n u s c r i p t a n d to a c k n o w l e d g e m y colleagues a n d the following scientific j o u r n a l s for their kind permission in allowing the r e p r o d u c t i o n of p u b l i s h e d figures: Drs. D. Albe-Fessard, G. Bernardi, N. A. Buchwald, M. B. Carpenter, J. Davies, M. D e L o n g , J. Feger, R. L . M . Faull, T. L. Frigyesi, J. Hore, D. P. P u r p u r a , M. Y o s h i d a ; Brain Research, Electroencephalograpy and

Clinical Neurophysiology, European Journal of Pharmacology, Experimental Brain Research, Experimental Neurology, Journal of Comparative Neurology, Journal of N europhysiology, Journal of Physiology, Research Publications of the Association of Research into Nervous and Mental Diseases, Neuroscience, Science. This article was written a n d s u b m i t t e d in final form while the a u t h o r was in receipt of a g r a n t from N I M H 5 - T O 1 - M H - 0 8 3 9 4 - 1 3 at D u k e University, a n d while a staff m e m b e r of the U n i v e r s i t y of Arizona, T u c s o n .

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