Anatomy, physiology, and pharmacology of the basal ganglia

~~~

0733-8619/01 $15.00 + .OO

MOVEMENT DISORDERS

ANATOMY, PHYSIOLOGY, AND PHARMACOLOGY OF THE BASAL GANGLIA Alexia E. Pollack, PhD

Voluntary movement is regulated by complex feedback loops that involve the cortex, the thalamus, and the basal ganglia; a group of five interconnected nuclei in the basal forebrain. The basal ganglia consist of the caudate and putamen, the internal and external segments of the globus pallidus (GPi and GPe), the subthalamic nucleus (STN), and the substantia The caudate and putamen together constitute the stianigra (SN).48,49,61 tum, the primary input structure of the basal ganglia. The striatum receives two major inputs, a massiveexcitatory glutamatergic input from most areas of the cerebral cortex, and a dopaminergic input from the substantia nigra pars compacta ( S N C ) . ~In, ~addition, ~ the stiatum receives inputs from the amygdala and thalamus (glutamate) and the raphe (~erotonin).4~,~' The principal output nuclei of the basal ganglia are the substantia nigra pars wticulata (SNr) and GPi (entopeduncular nucleus [EPI in rodent^).^,",^' The output nuclei of the basal ganglia, SNr and GPi, tonically inhibit the ventral anterior and ventral lateral motor nuclei of the thalamus, thereby reducing excitatory thalamic innervation of cortical motor areas.'**Movement occurs when the thalamus is disinhibited, facilitating excitation of cortical motor areas resulting in increased motor output to the brain stem and spinal cord. Human movement disorders with underlying pathology in the basal ganglia provide the most compelling evidence supporting a role of the basal ganglia in regulating motor function. Two examples at the extremes of the continuum are Parkinson's disease with its severe hypokinesia and Huntington's disease with its choreaform-type hyperkinesia.' The motor symptoms associated with these disorders are the consequence of the degeneration of specific populations of neurons in different basal ganglia From the Departmentof Biology, University of Massachusetts-Boston, Boston, Massachusetts NEUROLOGIC CLINICS VOLUME 19 NUMBER 3 AUGUST 2001

523

structures: dopamine neurons of SNc in Parkinson’s diseaseMand striatal output neurons in Huntington’s disease.%Pathology within structures of the basal ganglia not only serves to highlight the contribution of this system in regulating motor function, but also provides the basis for a variety of animal models for these human disease^.'^*^ BASAL GANGLIA CIRCUITRY

An elegant model of basal ganglia circuitry, put forth a decade ago, posits that voluntary movement is regulated by the activity of two opposing pathways which connect the striatum to the output nuclei of the basal ganglia (SNr/GPi) (Figure l).’** The “direct pathway” consists of a distinct population of striatal projection neurons, which send an inhibitory gamma-aminobutyric acid (GABA) projection directly to the SNr/GPi output nuclei. In contrast, the “indirect pathway” consists of a separate A CorhX

Bn

mom

B

1

Bnl

Figure 1. The circuitry of the basal ganglia. A, Model of basal ganglia circuitry from 1990, which highlights the direct and indirect pathways. 8, Current model of basal ganglia circuitry, which includes connections between GP, STN, and other nuclei. Projectionsfrom SNc and thalamus to STN are not shown. Shaded arrows = excitatory pathways; solidarrows = inhibitory pathways. SNc = substantia nigra pars compacta; GP = globus pallidus; STN = subthalamic nucleus; SNr/GPi = substantianigra pars reticulata/globuspallidus internal segment; Glut = glutamate; DA = dopamine; ENK = enkephalin; SP = substance I? (Adapted from Figure 2, Alexander GE, Crutcher MD,Functionalarchitecture of basal ganglia circuits: neuralsubstrates of parallel processing. Trends Neurosci. 13:266,1990;with permissionfrom Elsevier Science).

ANATOMY, PHYSIOLOGY, AND PHARMACOLOGY OF THE BASAL GANGLIA

525

population of striatopallidal neurons, which send an inhibitory GABAergic projection to the GPe. These external pallidal neurons, in turn, send a GABAergicprojection to the STN,which sends an excitatory glutamatergic projection to the SNr/GPi output nuclei. The SNr/GPi output nuclei send an inhibitory GABAergic projection to the motor nuclei of the thalamus, which sends an excitatory glutamatergicprojection to cortical motor areas. The SNr also influences oculomotor function through projections to the superior colliculus and dorsal medial thalamus.@ The influence of the direct and indirect pathways on cortical control of motor behavior can be predicted, based on the circuitry of the basal ganglia (see Figure 1).Activation of these two pathways exerts opposite effects on the activity of the output nuclei of the basal ganglia, and thereby produces antagonistic effects on thalamocortical activity.’,’ For example, activation of the direct pathway leads to GABA-mediated inhibition of SNr/GPi leading to an increase in motor behavior caused by disinhibition of the thalamus. In contrast, activation of the indirect pathway leads to GABA-mediated inhibitionof the GPe, attenuatingthe activity of GABAergic pallidal neurons, thereby disinhibiting the STN.Disinhibition of the STN leads to glutamatemediated excitation of the SNr/GPi, increased inhibition to the thalamus, and decreased motor activity. In summary, activation of the direct pathway inhibits SNr/GPi while activation of the indirect pathway excites SNr/GPi. Therefore, voluntary movement is mediated by a balance between the activity of these two opposing pathways which determines whether or not the basal ganglia issue instructions for motor activities to proceed. Recent anatomical evidence supports an added degree of complexity of basal ganglia circuitry that extends beyond the direct and indirect pathways. Most notably, these findings highlight additional roles for two indirect pathway nuclei: the STN and GPe (see Figure 1). Current models of basal ganglia circuitry include a more independent role for the STN, since this nucleus also receives direct inputs from cortical motor areas, intralaminar thalamus, SNc, and r a ~ h e . 4 ~The , ~ ’STN itself projects to the GPe, striatum, SNc, as well as projecting to the basal ganglia output nuclei, SNr/GPi.49,61 Recent evidence suggests that the GPe does not simply serve as a link between the striatumand the STN.The GPe itself sends direct projections to the GPi/SNr and the reticular nucleus of the thalamus,”*61 suggesting that this nucleus is in a position to regulate basal ganglia function through circuits that are distinct from the indirect pathway. It is a matter of some controversy as to how synaptic information that passes through the basal ganglia is processed. One theory suggests that there is sipficant convergence of synaptic inputs, which results in a progressive funneling of information. There is a significant reduction in neuronal densities from the striatum (lP-10’ neurons) to the output nuclei GR/EP (103-105 and this observation, together with the large dendritic arbors of pallidal neurons,5’ lends support to the convergence of striatal inputs onto a limited number of postsynaptic neurons.61However, a second theory suggests that synaptic information remains largely segregated and is processed by separate, parallel pathways within the basal

526

POLLACK

ganglia. This theory is supported by recent elechophysiologic evidence in primates using multiple simultaneous recordings of pallidal neurons! Dopamine denervation in these animals abolishes this segregated processing, thereby suggestingthat dopamineplays a significantrole in regulating the flow of information through the basal ganglia.' BASAL GANGLIA PHYSIOLOGY

The neurons in the basal ganglia display a range of basal physiologic firing rates and demonstrate distinct changes in neuronal firing relative to motor activity." Most striatal projection neurons display very low spontaneous activityl3with membrane potentials that fluctuatebetween a slightly depolarized "upstate" and a hyperpolarized "down-state".78Striatalneurons demonstrate sigxuficant increases in their firing rate prior to movement, caused by the release of glutamate from corticostriatal neurons? In contrast, pallidal neurons display one of two types of spontaneous bursting activity, with firing rates that either increase or decrease in relation to motor activity.I4Neurons in the STN display moderate basal activity76and generally increase their firing rate prior to movement." Dopaminergicneurons of the SNc display low spontaneousactivity,%which is not correlated with motor activity? In contrast, neurons of the basal ganglia output nuclei, SNr/GPi, demonstrate high basal firing ratesI4with excitatory drive from the STN.37SNr/GPi neurons either increase or decrease their firing rate after movement has begun, supporting the notion that the output of the basal ganglia does not play a significant role in movement i n i t i a t i ~ n . ~ ~ Furthermore, the electrophysiologicresponse of individual SNr/GPi neurons is often complex and likely reflects integration of synaptic information from both the direct and indirect pathways!' NEUROTRANSMITTER AND RECEPTOR LOCALIZATION

The primary neuronal cell type in the striatum is the medium spiny neuron, so named because of the size of its cell body (12-20 micrometers in diameter) and the presence of spines on its dendrites.%These medium spiny neurons account for 90%-95% of striatal neurons, and constitute the striatal projection neurons. Other populations of striatal neurons include large, aspiny cholinergic interneurons; as well as separate populations of interneurons that contain GABAVor the neuropeptide somatostatin." Staining for certain neumhemical markers results in the definition of two distinct anatomical compartments in the striatum: patches (striosomes) and matrix."*29High densities of mu opiate receptor binding33and low levels of acetylcholinesterase staining29 define patches (striosomes), whereas the surrounding matrix is defined by high levels of the calcium binding protein, ~ a l b i n d i nNeurons .~~ in these compartments have distinct afferent and efferent relationships with other structures in the basal ganglia. For example, patch and matrix compartments receive cortical

ANATOMY, PHYSIOLOGY, AND PHARMACOLOGY OF THE BASAL GANGLLA

527

inputs from neurons that reside in separate zones of layer V with deeper neurons projecting to patches and more superficial neurons projecting to matrix.= Likewise, separate zones of dopaminergic neurons in the SN project to patches and matrixz6and, in turn,striatal output neurons project to distinct regions in the SN, with the patch neurons projecting to SNc and matrix neurons projecting to SNr.22 Both the direct and indirect striatal output pathways arise from separate populations of medium spiny neurons that share morphological similarities. All medium spiny neurons contain the inhibitory neurotransmitter GABA,= but each striatal output pathway co-expresses different neuropeptides. Direct pathway (striatonigral) neurons contain the neuropeptides substance P and dynorphin, while indirect pathway (striatopallidal)neurons contain enkephalin." These output neurons are evenly distributed throughout the striatum,u and to patch and matrix compartments.5I Medium spiny neurons also have extensive axon collaterals that aw thought to participate in synaptic interactions both within and outside of the striatum.48*6z Dired and indirect pathway neurons express different dopamine receptor subtypes, with D1 receptors localized to striatonigral neurons and D2 receptors localized to striatopallidal neurons.25,31*32,41,* An estimated 5% of striatal projection neurons express both D1 and D2 receptors,@but this low estimate has been the subject of D3, D4, and D5 dopamine receptors have been cloned,@ but unlike D1 and D2 receptors they are not appreciably expressed in the dorsal striatum.E,@Dopamine D1 and D2 receptor subtypes modulate striatal neuropeptide expression in opposite directions with D1 stimulation necessary to maintain basal levels of substance P and dynorphin in striatonigral neurons, and D2 stimulation tonically inhibiting enkephalin synthesis.E* 41*81 Conversely, depletion of striatal dopamine content by a neurotoxic lesion or treatment with dopamine antagonists decreases levels of substance P and dynorphin but increases enkephalin levels in the striatum.25*44,yI,81 Striatal neurons express a variety of different neurotransmitter recep tors, which reflect the neurochemical diversity of the inputs to this structure. Both NMDA and non-NMDA ionotropic glutamate receptors$, 64,68*69 as well as several subtypes of metabotropic glutamate receptors,'O are expressed by striatal neurons with variations observed in the type of ionotropic receptor subunit or metabotropic receptor sub e expressed in medium spiny neurons and striatal i n t e r n e u r ~ n s ? ~Three ,~,~ subtypes ~ ~ ~ of muscarinic cholinergic receptors are expressed in striatum. The ml and m4 receptors are found in both cholinergic interneurons and medium spiny neurons, with only 40% of striatopallidal neurons expressing the m4 recept~r.~, 75 Cholinergic interneurons express m2 muscarinic receptors? 75 as well as D2 dopamine receptors and, to a smaller extent, D1 dopamine receptors.30,"," A1 and M a adenosine receptors are differentially expressed in medium spiny neurons with A1 receptors co-localized with D1 receptors in striatonigro-entopeduncular and A2a receptors and D2 receptors co expressed in striatopallidal Functionally, each adenosine receptor subtype a ears to oppose the effects of its co localized dopamine receptor subtype.lHIE.53

528

POLLACK

GLUTAMATE-DOPAMINE INTERACTION

The cortical input to the striatum is massive and topographically ordered, with sensory and motor cortices projecting to putamen, associative cortex projecting to caudate and rostra1 putamen, and limbic cortical areas projecting to the ventral striatum.48*61 Release of glutamate by cortical neurons has a uniformly excitatory effect on striatal neurons.'r2Therefore, most theories of basal ganglia function propose that glutamate drives striatal activity and dopamine modulates this activity by shifting the balance between hyperkinesia and hypokinesia.65Ultrastructural evidence suggests that glutamate and dopamine interact at the level of synaptic inputs to medium spiny neurons (Figure2). Excitatory cortical and thalamic afferents synapse mainly onto the heads of dendritic spines of medium spiny neurons, whereas nigrostriatal dopamine neurons synapse primarily onto the shafts of the same dendritic spines.7," These lindings are consistent with the notion that dopaminergic synapses are in an anatomical position to modulate glutamatergicinput to medium spiny neurons. Glutamate released by corticostriatal neurons activates both striatonigral and striatopallidal neurons.'**Consequently, glutamate stimulates

Figure2. Glutamatergic,dopaminergic, and cholinergic synaptic inputs onto a medium spiny striatal neuron. (AdaptedfromFigure 3, Smith AD, Bolam JP, Neural network of the basal ganglia as revealed by the study of synaptic connections of identified neurons. Trends Neurosci. 13:259, 1990 with permission from Elsevier Science).

ANATOMY, PHYSIOLOGY, AND PHARMACOLOGY OF THE BASAL GANGLIA

529

motor behavior through excitatory effects on the direct pathway and inhibits motor behavior through excitatoryeffects on the indirect pathway. In contrast, dopamine promotes motor behavior by its action on both the directand indirect pathways,',' since dopamine excites striatonigral neurons expressin D1 receptor and inhibits striatopallidal neurons expressing D2 receptors5*z*nTherefore, similar to glutamate, dopamine promotes motor activity in the direct pathway but, unlike glutamate, dopamine also promotes motor behavior in the indirect pathway through D2-mediated inhibition of striatopallidal neurons.',2,'' Consequently, in the absence of dopamine, striatopallidal neurons become hyperactive since the excitatory influenceof glutamate is no longer balanced by dopamine.',2,65*80 Attempts to counter this imbalance by administration of glutamate antagonists produces variable, dosedependent results, although glutamate antagonists can more reliably otentiate the motor effects of L-dopa in the dopamine depleted system. Although dopamine acting on both striatal output pathways promotes motor activity, the information conveyed by these pathways is slightly different. While D2 agonists are more potent than D1 agonists in stimulating motor behavior,65simultaneous activation of both D1 and D2 receptors is necessary for the strongest motor response in the intact basal ganglia.8tn In contrast, following dopamine denervation, D1 and D2 dopamine receptors appear to function more independently with significant motor activity observed following administration of either D1 or D2 selective a g ~ n i s t s ; ~ , ~ ' however, even in the dopamine depleted system, D1 and D2 synergism is still noted.50,59*e

69

ACETYLCHOLINE-DOPAMINE INTERACTION

Although cholinergic interneurons comprise only 1%-2% of the total neuronal population in the striatumImthese interneurons possess extensive projections and large dendritic fields.= Cholinergic interneurons synapse directly onto medium spiny neurons with syaptic contacts found on spines, dendrites, and cell bodies (Figure 2). Cholinergic interneurons themselves receive input from the thalamus/cortex (glutamate), medium spiny neurons (GABA/substance PI, and SNc (dopamine).'6 Cholinergic neurons express both NMDA and non-NMDA glutamate and appear to be especially sensitive to the excitatory effects of glutamate.n Dopamine differentially regulates striatal cholinergic function with stimulation of D1 receptors increasing, and stimulation of D2 receptors decreasing acetylcholine release.I6These responses occur through D1 and D2 receptors expressed by cholinergic interneurons,30,43,75 as well as through D1-mediated substance P release from striatonigral axon collaterals.'6 A balance between acetylcholine and dopamine has been recognized as necessary for normal striatal function, thereby suggesting that acetylcholine usually opposes the effects of dopamine. Consistent with this notion, muscarinic antagonists can potentiate D1 r e ~ ~ n s e sor~ partially ,'~ substitute for D2 dopamine receptor ~timulation.~',Early pharmacotherapies for PD using cholinergic antagonists aim to restore this acetylcholine-dopamine

balance? ment

however, this approach is not as effective as dopamine replace-

SUMMARY

The basal ganglia influence cortical control of voluntary movement by regulating the activity of the motor nuclei of the thalamus. Since the output nuclei of the basal ganglia tonically inhibit the thalamus, the basal ganglia exert their motor promoting effect through disinhibition of the thalamus. The striatum (caudate-putamen) serves as the input structure of the basal ganglia receiving afferents primarily from the cortex and SNc. Striatal projection neurons form the direct and indirect pathways, which transmit information to the SNr/GPi output nuclei. Based on recently delineated connections between GP, STN, and other structures of the basal ganglia, there appear to be several indirect pathways. Analysis of neuronal densities suggest that there is a significant degree of synaptic convergence in the basal ganglia; however, there is also evidence supporting separate, parallel pathways of information flow. Striatal neurons display very low levels of spontaneous activity, whereas the output nuclei, SNr/GPi, have high basal firing rates, which provide tonic inhibition to the thalamus. While striatal neuronal firing increases prior to movement, the activity of SNr/GPi is more complex and reflects integration of inputs from both the direct and indirect pathways. The striatum can be divided into two separateanatomical compartments,called patch and matrix, each of which maintains distinct afferent and efferent relationships with other brain nuclei. All striatal projection neurons contain the inhibitory neurotransmitter GABA, but each striatal output pathway also contains distinct neuropeptides. Different dopaminereceptor subtypesare expressed by the separate populations of striatal output neurons with D1 receptors on striatonigral neurons and D2 receptors on striatopallidal neurons. Receptors for glutamate, acetylcholine, and adenosine are also present in the striatum, with variations observed in their expression in striataloutput neurons and cholinergic interneurons. Glutamate and dopamine directly influence striatal output neurons through synaptic inputs onto distinct portions of their dendrites. Glutamate and dopamine both promote motor behavior through excitatory effects on the direct pathway, but provide antagonistic effects on the indirect pathway since dopamine inhibits striatopallidal neurons. Cholinergic interneurons also regulate the activity of striatal output neurons and balance the influence of dopamine. References 1. Albin RL, Young AB, PenneyJ BThe functionalanatomyof basal ganglia disorders.Trends Neurosci 12366,1989 2. Alexander GE, Crutcher MD: Functional architecture of basal ganglia cirmits: neural

substrates of parallel processing. Trends Neurosci 13:266,1990

ANATOM, PHYSIOLOGY, AND PHARMACOLOGY OF THE BASAL GANGLIA

531

3.Alexander GE, Dehng MR, Strick PL Parallel organization of functionally segregated circuits linking basal ganglia and cortex. Ann Rev Neurosci 9357,1986 4. Bergman H, Feingold A, Nini A, et a1 Physiological aspects of processing in the basal ganglia of normal and parkinsonian primates. Trends Neurosci 21:32,1998 5. B e d V, Normand E, Bloch B Phenotypical characterizationof the rat striatal neurons expressing muscarinic receptor genes. J Neurosci 12:3591,1992 6. Bolam JP,Wainer BH, Smith AD. Characterizationof cholinergic neurons in the rat neostriatum. A combination of choline acetyltransferaseimmunocytochemistry, Golgi impTegnation and electron microscopy. Neuroscience 12711,1984 7. buyer JJ,Park DH, Joh TH,et al: Chemical and structural analysisof the relationbetween cortical inputs and tyrosine hydroxylasecontaining terminals in rat neostriatum. Brain Res 302267,1984 8. Braun AR, Chase TN. Obligatory Dl-M receptor coactivation and the generation of dopamine agonist related behavior. Eur J Pharmacol131:301,1986 9. Brumlik J,Canter G, DeLaTorreR, et a1A critical analysisof the effectsof trihexyphenidyl (Artane)on the componentsof the parkinsoniansyndrome.J Nerv Ment Dis 138424,1964 10. Burns BD, DeJong D, SolisQuimga OH: Effects of trihexyphenidyl hydrochloride (Artane) on Parkinson's disease. Neurology 1413,1964 11. Carlson J, Bergstrom DA, Demo S, Walters JRNigrostriatallesion alters neurophysiological responses to selective and nonselective D1 and D2 dopamine agonists in rat globus pallidus. Synapse583,1990 12. Cotzias GC, VanWoert MH, Schiffer LM: Aromatic amino acids and modification of parkinsonism. N Engl J Med 2767374,1967 13. Crutcher MD, Delong MR: Single cell studies of the primate putamen. I. Functional organization. Exp Brain Res 53233,1984 14. Dehng MR:Activity of pallidal neurons during movement. J Neurophysiol34:414,1971 15. Dehng MR: Primate models of movement disorders of basal ganglia origin. Trends Neurosci 13281,1990 16. DiChiara G, Morelli M, Consolo S Modulatory functions of neurotransmitters in the striatum: ACh/dopamine/NMDA interactions. Trends Neurosci 17228,1994 17. DiFiglia M,Aronin N: Ultrastructural features of immunoreactivesomatostatin neurons in the rat caudate nucleus. J Neurosci 21267,1982 18. Ferre S,O'Connor W, Fuxe K, et al:The striatopallidalneuron-a main locus for adenosine dopamine interactionsin the brain. J Neurosci 135402,1993 19. Ferre S,(YConnorW, Svenningsson P,et al: Dopamine D1 receptor-mediated transmission in the rat strioentopeduncular pathway and its modulation by adenosine A1 receptormediated mechanisms. Eur J Neurosd 8:1545,1996 20. Fink JS,Weaver DR, Rivkees SA, et al: Molecular cloning of the rat A2 adenosine receptor: selective cwxpression with D2 dopamine receptors in rats striatum, Mol Brain Res 14 186,1992 21. Georgopoulos AP, DeLong MR, Crutcher MD Relation between parameters of step tracking movements and single cell discharge in the globus pallidus and subthalamic nucleus of the behaving monkey. J Neurosci 31586,1983 22. Men CR The neostriatal mosaic: I. Compartmental organization of projections from shiatum to substantia nigra in the rat. J Comp Neurol236:4!54,1985 23. Gerfen CR The neostriatal mosaic: striatalpatch-matrixOrganization is related to cortical lamination.Science 246335,1989 24. Gerfen CR, Bainbridge KG, Miller JJ: The neoshiatal mosaic: compartmentaldistribution of calcium binding protein and paravalbumin in the basal ganglia of the rat and monkey. Proc Natl AcadSci USA 828780,1985 25. Gerfen CR,Engber TM, Mahan LC, et al: D1 and D2 dopamie receptor I.egulated gene expression of striatonigral and striatopallidal neurons. Science 250:1429,1990 26. Gerfen CR, Herkenham M, Thilbault J: The neostriatal mosaic: II. Patch- and matrixdirected mesostriatal dopaminergic and nondopaminergic systems. J Neurosa 73915, 1987 27. Gerfen CR, Young WS Distribution of striatonigral and striatopallidal neurons in both patch and matrix compartments:an in situ hybridization histochemistry and fluorescent retrograde tracing study. Brain Res 460:161,1988

532

POLLACK

28. Grace AA, Bunney BS: Intracellular and extracellular electrophysiology of nigral dopaminergic neurons-1. Identification and characterization. Neuroscience 10:301,1983 29. Graybiel AM, Ragsdale JCW: Histochemical distinct compartments in the striatum of human, monkey, and cat demonstrated by acetylcholinesterasestaining.Proc Natl Acad Sci USA 755723,1978 30. Guennoun R, Bloch B: Ontogeny of D1 and DARPP-32 gene expressionin the rat striatum: an in situ hybridization study. Mol Brain Res 12131,1992 31. Harrison MB, Wdey RG, Wooten G F Selective localization of striatal D1 receptors to striatonigralneurons. Brain Res 528317,1990 32. Hanison MB, Wiley RG, Wooten GF Changes in D.2 but not D1 receptor binding in the striatum following a selective lesion of striatopallidal neurons. Brain Res 590:305, 1992 33. HerkenhamM, Pert CB Mosaic distribution of opiate receptors,parafascicularprojections and acetylcholinesterasein rat striatum. Nature 291:415,1981 34. Homykiewiu 0 Dopamine (Shydroxytyramine) and brain function. Pharmacol Rev 18:925,1966 35. Kemp JM, Powell Tps: The structure of the caudate nucleus of the cat light and electron microscopic study. Trans R Soc London (Biol.)262383,1971 36. Kita H, Kitai ST Glutamate decarboxylase immunoreactiveneurons in rat neostriatum. Their morphological types and populations. Brain Res 477346,1988 37. Kitai ST, Kita H Anatomy of physiology of the subthalamic nucleus: a driving force of the basal ganglia. In Carpenter MB,Jayaraman A (eds):The Basal Ganglia 11-Structure and Function: Current Concepts. New York, Plenum Press, 1987, p 357 38. Kopin IJ: The pharmacology of Parkinson's disease therapy: An update. Annu Rev Pharmacol Toxicol32467,1993 39. Landwehnneyer GB, Standaert DG, Testa CM, et a1 NMDA receptor subunit mRNA expression by projection neurons and interneurons in rat striatum. J Neurosci 155297, 1995 40. L.e Moine C, Bloch B: D1 and M dopamine receptor gene expression in the rat striatum: sensitive cRNA probes demonstrate prominent segregation of D1 and D2 mRNAs in distinct populations of the dorsal and ventral striatum. J Comp N e w 1 355418, 1995 41, Le Moine C, Normand E, Bloch B Phenotypical characterization of the rat striatal neurons expressing the D1 dopamine receptor gene. Pmc Natl Acad Sci USA 88:4205,1991 42. Le Moine C, Normand E, Guitteny AF, et a1 Dopamine receptor gene expression by enkephalin neurons in the rat forebrain, Proc Natl Acad Sci USA 87230,1990 43. Le Moine C, Tion F, Bloch B D2 dopamine receptor gene expression by cholinergic neurons in the rat striatum. Neurosci Lett 117248,1990 44. Li SJ, Jiang HK, Stachowiak MS, et a1 Muence of nigrostriatal dopaminergic tone on the biosynthesis of dynorphin and enkephalin in the rat striatum. Mol Brain Res 8219, 1990 Basal Ganglia. In Zigmond MJ, Bloom FE, Landis X, Roberts JL, Squire LR 45. Mink JW: (eds):Fundamental Neuroscience.San Diego, Academic Press, 1999, p 951 46. Morelli M, Fenu S, Cozzolino A, et a1 Blockade of mwaxinic receptors potentiates D1 dependent turning behavior and c-fos expression in 6-hydroxydopamine-lesionedrats but does not influence M mediated responses.Neuroscience 53673,1993 47. Nisenbaum LK, Kitai ST,Gerfen CR Dopaminergic and muscarinic regulation of striatal enkephalin and substance P messenger RNAs following striatal dopamine denervation: effects of systemic and central administration of quinphle and scopolamine. Neuroscience 63:435,1994 48.Parent A, Hazrati LN: Functional anatomy of the basal ganglia. I. The cortical-basal ganglia-thalamocorticalloop. Brain Res. Rev. 2091,1995 49. Parent A, Hazrati LN: Functional anatomy of the basal ganglia. II. The place of s u b thalamic nucleus and external pallidum in basal ganglia circuitry. Brain Res Rev 20128, 1995 50. Paul ML, Graybiel AM, David JC, et al: D1-like and D2-like dopamine receptors synergistically activate rotation and c-fos expression in the dopamine-depleted striatum in a rat model of Parkinson's disease. J Neurosa 123729,1992

ANATOMY, PHYSIOLOGY, AND PHARMACOLOGY OF THE BASAL GANGLIA

533

51. Penny GR, Afsharpour S, Kitai ST The glutamate decarboxylase-, leuane enkephalin-, methionine enkephalin- and substance P-inmunoreactive neurons in the neostriatum of the rat and cat evidence for partial population overlap. Neuroscience 171011,1986 52. Percheron G, Yelnik J, Francois C A Golgi analysis of the primate globus pallidus. 111. Spatial organization of the striato-pallidal complex. J Comp Neurol 227214,1984 53. Pollack AE, FinkJ S Adenosine antagonists potentiate D2 dopamine-dependent activation of Fos in the striatopallidal pathway. Neuroscience 68721,1995 54. Pollack AE, Wooten G F Differential regulation of striatal preproenkephalin mRNA by D1 and D2 dopamine receptors. Mol Brain Res 12:111,1992 55. Pollack AE, Wooten G F D2 Dopaminergic regulation of striatal preproenkephalin mRNA levels is mediated in part through cholinergic interneurons. Mol Brain Res 1335,1992 56. Purdon SE, Mohr E, Ilivitsky V, et al: Huntington's disease: pathogenesis, diagnosis and treatment. J Psychiatry Neurosci 19359,1994 57. Ribak CE, Vaughn JE, Roberts E TheGABA neurons and their axon terminals in rat corpus stratum as demonstrated by GAD immunohistochemistry. J Comp Neurol187261,1979 58. Richardson PJ, Dixon AK, Lee K, et ak Correlating physiology with gene expression in striatal cholinergic neurons. J Neurochem 74839,2000 59. Robertson GS, Robertson HA: Synergistic effects of D1 and D2 dopamine agonists on turning behavior in rats. Brain Res 384387,1986 60.SchiffmannSN, Vanderhaeghen JJ: Adenosine A2 receptors @ate gene expression of striatoDallidd and shiatonimal neurons. 1 Neurosci 131080.1993 6oa.Sibleyb R , Monsrna FJ: Moi&ular biolo& of dopamine receptors. Trends Phannacol Sci 1361,1992 61.Smith Y, Bevan MD, Shink E, et ak Microcircuitry of the direct and indirea pathways of the basal ganglia. Neuroscience 86:353,1998 62.Smith AD, Bolam J P Neural network of the basal ganglia as revealed by the study of synaptic connections of identified neurons. Trends Neurosci 13259,1990 63. S o d a PK, Manzino L, Heikkila RE: Interactions of D1 and D2 dopamine receptors on the ipsilateral vs. contralateral side in rats with unilateral lesions of the dopaminergic nigrostriatal pathway. J Phannacol Exp Ther 247180,1988 64. Standaert DG, Testa CM, Young AB, et al: Organization of N-methyl-Baspartate glutamate receptor gene expression in the basal ganglia of the rat. J Comp Neurol 343:1, 1994 65.Starr Ms: Glutamatedopamine D1/D2 balance in the basal ganglia and its relevance to Parkinson's disease. Synapse 19264,1995 66.Surmeier DJ, Eberwine J, Wilson CJ, et al: Dopamine receptor subtypes colocalize in rat striatonigral neurons. Proc Natl Acad Sci 89:10178,1992 67.Surmeier DJ, Song WJ, Yan Z Coordinated expression of dopamine receptors in neoshiatal spiny neurons. J Neurosci 166579,1996 68.Tallaksen4reene SJ, Albin RL Localization of AMPA-selective excitatory amino acid receptor subunits in identified populations of shiatal neurons. Neuroscience 61509,1994 69. Tallaksenxreene SJ, Wiley RG, Albin R L Localization of striatal excitatory amino acid binding site subtypes to striatonigral projection neurons. Brain Res 594165,1992 70. Testa CM, Standaert DG, Young AB, et ak Metabotropic glutamate receptor mRNA expression in the basal ganglia of the rat. J Neurosd 143005,1994 71.T r u m a n lM. Wooten G F SelectiveDl and D2 doDamine aeonists differentiah alter basal ganklia giuc-&e utilization in rats with unilaterh 6-hydGxydopamine subsiantia nigra lesions. J Neurosci 72927,1987 72. ' h e r y MJ, Thompson LA,Walter JR: SKF 38393 increases the excitability of striatal neurons ipsilateral to 6-hydroxydopamine-induceddopamine cell lesions and decreases the excitability of neurons in contralateral striatum in vitro.Eur J NeuFosci Supp. 4146,1991 73. Walters JR,Bergstrom DA, Carlson JH, et al: D1 dopamine receptor activation required for postsynaptic expression of D2 agonist effects. Science 236:719,1987 74. Wang JQ, McGinty J F Scopolamine augments c-fos and zif/268 messenger RNA expression induced by the fullD1 dopaminereceptoragonist SKF-82958in the intact rat striatum. Neuroscience 72601,1996 75. Weiner DM, Levey AI,Brann MR: Expression of muscarinic acetylcholine and dopamine receptor mRNAs in the rat basal ganglia. Proc Natl Acad Sci USA 877050,1990

76. W~chmannT, Bergman H, DeLong MR the primate subthalamic nucleus. I. F ~ n c t i o ~ l properties in intact animals. J Neurophysiol72494,1994 77. Wilson CJ, Chang HT, Kitai ST:Firing patterns and synaptic potentials of identified giant aspiny interneurons in the rat neostriatum. J Neurosci 10508,1990 78. Wilson CJ, Kawaguchi Y: The origins of two-state spontaneous membrane potential fluctuations of neostriatal spiny neurons. J Neurosci 162397,1996 79. Woolf NJ, Butcher L L Cholinergic neurons in the caudate-putamen complex proper are intrinsically organized: a combined Evans blue and acetylcholinesteraseanalysis. Brain Res Bull 7487,1981 80. Wooten GF, Collins RC: Metabolic effects of unilateral lesion of the substantia nigra. J Neurosci 1:285,1981 81. Young WS, Bonner TI, Brann MR Mesencephalic dopamine neurons regulate the expression of neuropeptide mRNAs in the rat forebrain. Proc Natl Acad Sci USA 83:9827, 1986

Address reprint requests to: Alexia E. Pollack, PhD Department of Biology University of Massachusetts, Boston 100 Morrissey Boulevard Boston, MA 02125393