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Blockade by frontocortical lesion of reciprocal regulation between the two nigrostriatal dopaminergic pathways
0306-4522/84 $3.00 + 0.00 PergamonPress Ltd 0 1984 IBRO
NeuroscienceVol. 13, No. 1, pp. 53-59, 1984 Printedin Great Britain
BLOCKADE BY FRONTOCORTICAL LESION OF RECIPROCAL REGULATION BETWEEN THE TWO NIGROSTRIATAL DOPAMINERGIC PATHWAYS V.
LEVIEL, C. KERNY,
C.
BARBERIS,
B.
GUIBERT
and F.
DAUDET
Laboratoire de Physiologie Nerveuse, Dipartement de Neurophysiologie Appliquee, C.N.R.S., 91190 Gif sur Yvette, France
Abstract-Tritiated dopamine synthesized from tritiated tyrosine was estimated simultaneously in the two caudate nuclei and the two substantia nigrae of cats anaesthesized with halothane. In control animals, the electrical stimulation of the right forelimb enhanced dopamine release in the right caudate nucleus and decreased dopamine release in the right substantia nigra. Opposite effects were observed in the contralateral structures. Left nigral application of d-amphetamine produced the same effect. However in cats with extensive lesions of the left pericruciate cortex, an increase in the release of dopamine in the left substantia nigra was the only detectable effect of these two treatments. These results suggest that the cortical structures are involved not only in the transfer of information between the two dopaminergic pathways but are also involved with regulation of the release of dopamine in the striatum originating in the substantia nigra. With regard to the role of the thalamic structures in this transfer of information, it is proposed that the thalamostriatal control of the release of dopamine previously suggested is closely dependent on cortical activity.
functionally linked and similar conclusions resulted from electrophysiological data.” Morphological support of this interhemispheric relationship is not well defined but Levine et al.” and Cheramy et ~1.~concluded that some non-specific thalamic nuclei could act as a fulcrum between the activity of the two nigrostriatal dopaminergic pathways. Cortical structures were also implicated in the regulation of striatal dopamine release, particularly the frontal cortical area. The corticostriatal pathway is well defined by anatomical data and if no part of the striatum is under the sole influence of one functional area of the neocortex, the projections of the sensory motor cortex are the most substantial. In 1978 Nieoullon et ~1.‘~ described a bilateral increase of the release of dopamine in the head of the caudate nucleus in response to electrical stimulation of the sensory motor cortex. More recently Scatton et al.” observed a decrease of DA content in the striatum of rat with lesion of ipsilateral frontal cortex. Electrophysiological data suggest that the cortical input to the striatum is both monosynaptic and facilitatory.2,3 In fact lesion of the frontal cortex produced a marked slowing of caudate neuronal firing.’ Moreover striatocortical inputs are bilateral and there is good evidence for a glutamatergic nature of their neurotransmission.‘.8~‘o Thus in an attempt to test the role of the pericruciate cortical area on the relationship between the two nigrostriatal dopaminergic paths, we examined the effect of a lesion of the sensory motor cortex on two paradigms in which this relation was evidenced:
In 1977 Nieoullon et ~1.‘~ observed a release of dopamine (DA) originating from the dendrites of dopaminergic cells in the substantia nigra. Dopamine, which inhibits the ascending dopaminergic cellq9 was thus considered to be one of the major mechanisms regulating the release of DA in the ipsilateral caudate nucleus. Pharmacologically induced alterations of the release of DA in the substantia nigra resulted consistently in opposite variations of DA release in the striatum.4 Thus, d-amphetamine applied to the substantia nigra through a push-pull cannula superfusing this structure induced a local increase of the release of DA and a decrease in the ipsilateral caudate nucleus, probably due to an inhibition of the dopaminergic cells. However, the simultaneous observation of the release of dopamine in the two caudate nuclei and the two substantia nigrae led Leviel et ~1.‘~ to conclude in 1979 that DA released in the substantia nigra was not acting only on the ipsilateral dopaminergic cells but was able to interfere with contralateral activity of the homologous tract. In fact nigral increase of DA release in one substantia nigra (SN) induced by local application of d-amphetamineI or contralateral sensorial stimulation” resulted not only in a decrease of DA release in the homolateral caudate nucleus (CN) but in an increase in the contralateral CN presumably through a decrease of DA release in the SN. Thus the two nigrostriatal dopaminergic pathways appeared as Abbreviations: CN, caudate nucleus; DA, dopamine; SN, substantia nigra. 53
54
V. Levier ef at.
the nigral application noxious Materials
sensorial
of ~-amphetamine stimulation.
and a non-
EXPERIMENTAL PROCEDURES
L-3,5-[3H]Tyrosine (50 Ci/mM) originated from NEN or Amersham. Halothane was obtained from I.C.I. Pharma (Enghien, France) and d-amphetamine from Cooper (Melun, France). Biological model
Cats, weighting from 2 to 3 kg were used in this study. Under deep (> 3%) halothane anaesthesia, tracheotomy and cannulation of femoral artery was performed. Animals were maintained in the stereotaxic position of a Horsley-Clarke apparatus, (LPC, France) using two bars fixed with screws and acrilyc cement in the occipital and frontal bone. This low pain procedure allowed the maintenance of light anaesthesia with 1.5% halothane during the superfusion. Alveolar COz, arterial blood pressure, electrocardiogram and temperature were recorded during the experiment. Arterial PCO,, POz and pH were also controlled during the experiment. Cortical lesion
Lesions of the left pericruciate cortex were achieved during deep halothane anaesthesia (3.5%) by successive light suctions applied to a maximum depth of 2 mm, and over an area of 4-6 mm2. Lesions affected the superficial part of the anterior and posterior part of the left sigmoidal girus. Histological control of the lesions was performed after each experiment. Depth and extent of the lesions obtained are described in Fig. 1. Imp~an~at~#~0~ Pugh-pull c~~u~ue
quantities found in the six fractions collected just before the treatment was used as an individual control value (lOO~~$. Each successive fraction was then expressed as a percentage of this hasal v&e. Comparisons were made between the means of the values obtained from unlesioned (controls) and lesioned animals. Two-tailed Student’s I test was employed for the statistical analysis. Histological controls
At the end of each experiment, the brain of the cat was perfused with 10% formalin through the carotid artery. Serial frontal sections were stained with cresyl violet: the emplacement of cannulae and the extent of the lesions were then examined (Fig. 1B).
RESULTS
Cortical lesions were made 2 h before the beginning of the superfusion. Compared to controls no alteration of the stability of the release of [-‘HIDA was detected; furthermore the mean of the absolute level of the collected labelled DA did not differ from those obtained from control cats (about 300 pCi in SN and 55OpCi in CN). Thus the cortical lesions did not affect, in these conditions, the spontaneous release of the newly synthesized DA from the nerve terminals of the caudate nuclei or from the dendrites of the substantia nigrae.
Four push-pull cannulae were stereotaxically implanted in the two caudate nuclei (CN) and the two substantia nigrae (SN); coordinates: CN: A = 16, L = 4.5, H = 5 and SN: A = 4, L = 4.5, H = - 5 (from atlas of Jasper and Ajmone-Marsan”). For the positioning of the nigral cannulae, bipolar concentric electrodes were substituted in the mandrels of the nigral cannulae. Lemniscal and nigral electrophysiological responses evoked by electrical stimulations of the contralateral forepaw were then recorded until the tip of the electrode reached the desired structure. Supecfusion procedure and biochemical analysis
The four push-pull cannulae were continuously supplied with artificial ~rebrospinal fluid (in mM: NaCl, 126.5; NaHCO,, 27.5; KCI, 2.i; KH,PC),, 0.5; CaC&, I .l: MgC&, 0.80: NaSO,. 0.5: elucose. 5.9). adjusted to OH 7.3 with 0,-&O, ?9S/? v/vj kixture, aid cintaining
From each cannula and each animal the mean of [‘HIDA
TME
cm”,
Fig. 2. Effects of cortical lesion on the DA release alterations during right forelimb stimulation. [‘H]Dopamine was estimated in 10 min-successive superfusate fractions, collected simuItaneously from the four implanted push-pull cannulae supplied with L-3,5-~3H]tyros~ne in artificial cerebrospinal fluid. The paw of the right forelimb was stimulated for the 10 min of the seventh fraction (square pulses, 0.5 ms, 0.2 Hz. 2-3 V). a, controls; A, lesioned animals. In each animal and for each cannula, [3H]DA in each successive fraction was expressed as a percentage of an average spontaneous release calculated from the six fractions collected before the stimulation. Data are the mean + SEM of results obtained with n animals. (n = 7 for controls. n = 8 for lesioned cats.) *P < 0.05 when compared with corresponding controls values obtained in unlesioned animals. L, left; R, right.
B
_
Fig. 1. Extent of the pericruciate cortical lesion. (A) Schematic drawing showing the extent of damage (darkened area) after removal of the pericruciate cortex. (B) Vertical section of a lesioned animal showing depth of cortical lesion.
55
57
Cortical control of dopamine release Eflects of right sensory stimulation on lesioned animals
(Fig. 2) In control cats electrical stimulations of the right forelimb induced asymmetric changes in the release of i3HfDA from the two caudate nuclei and the two substantia nigrae: the stimulation induced an enhancement of the release from the ipsilateral caudate nucleus linked to a decrease in the corresponding substantia nigra. An opposite alteration appeared in the contralateral side with a decreased release of DA from the caudate nucleus probably due to an increase in the substantia nigra. In cats whose left pericruciate cortex had been lesioned, electrical stimulation of the right forelimb induced an increase in the [3H]DA released in the contralateral substantia nigra: this increase did not differ from the increase which had been obtained in the unlesioned cats. However, no effect of the sensory stimulation was detected in the three other structures, where the level of the spontaneous DA release stayed stable. Efsects of left nigral application of d-amphetamine on iesioned cats (Fig. 3)
~-Amphetamine, applied for 10min in the left substantia nigra of control cats, induced asymmetric changes in the four structures: the release of [3H]DA was enhanced locally in the left SN, but reduced in the ipsilateral CN, and opposite changes were observed in contralateral structures. In cortically le-
-w7.’ ..J
30
80
80
120
Fig. 3. Effects of cortical lesion on the DA release alterations during nigral appli~tion of ~-amphetamine. Experiments
were carried out as described in Fig. 2. d-Amphetamine was applied for the 10min of the seventh fraction. n , controls; A. lesioned animals, *, P i 0.05 when values obtained from lesioned animals (n = ?) were compared with corresponding control values obtained from unlesioned animals (n = 7). L, left; R, right.
sioned cats, d-amphetamine still produced a sharp increase of the release of DA in the left SN, but in spite of this important variation, the release of DA was not reduced in the ipsilateral CN. Furthermore the s~ntaneous release of DA was not affected in the contralateral structures after this nigral application of d-amphetamine in contrast to the effect in unlesioned animals. DISCUSSION
These results show that a lesion of the pericruciate cortex is without effect on the alteration of DA release in the SN produced by local application of d-amphetamine or contralateral forepaw stimulation. However, after such a lesion, this increase of the DA release in the SN is unable to induce either an ipsilateral decrease in the striatum or a contralateral expected increase. Furthermore the spontaneous release of DA in the contralateral SN was unchanged. These observations enphasise the major role played by the frontal cortex in regulating the release of DA in the extrapyramidal system. Role of the pericruciate cortex on the tonicai refease of dopamine
Surprisingly, the cortical lesion seems to have no effect on the tonic release of DA in the two caudate nuclei. In 1978 Nieoullon et al.” have shown, using a similar model, that electrical stimulation of the sensory motor cortex resulted in an increase of DA release in the two caudate nuclei. From this observation, these authors extended the excitatory role generally attributed to the corticostriate pathway onto the dopaminergic terminals. Thus, cortical lesion should result in a decreased release of dopamine in the striatum. However, we did not observe such a decrease, since the mean value of [3H]DA released every 10 min was not different from the mean value obtained in non-lesioned animals. This fact is not paradoxical for two reasons: first, the cortical lesions in our model were always performed 2 or 3 h before the beginning of the superfusion and this time should be sufficient to compensate for a putative decrease in the striatal release of dopamine. Second, the corticostriatal influence could be only an excitatory mechanism, not responsible for tonic release of DA in the striatum. The pericruciate cortex and alterations of the release of dopamine in the striatum
Paradoxically, after cortical lesion, we do not see a decrease of DA release in the striatum in spite of the increase in DA in the ipsilateral SN. The inhibitory action of DA on the nigrostriatal cells should result in such an alteration. Furthermore, contralateral sensorial stimulation also produce a nigral increase of the release of DA without affecting the
V. Leviel et al
58
corresponding striatal DA release. Similar observations have already been made, using the same biological model.‘-14 An increased release of DA in the substantia nigra induced by sensorial stimulation14 or local application of d( +)-amphetamine6 was without effect on the release of DA in the ipsilateral caudate nucleus on cats whose massa intermedia of the thalamus were sectioned. These results led the authors to propose the existence of a nigrothalamostriatal mechanism able to compensate for the inhibiton of the nigrostriatal cells induced by nigral DA. This compensatory mechanism may be under control of an uncharacterized thalamic relay. In fact, electrical stimulation of various thalamic nuclei has been shown to alter the release of DA in both the caudate nuclei and substantia nigrae.’ The proposed compensatory mechanism might be activated by way of the DA sensitive nigrothalamic tract, and normally inhibited at the thalamic level by frontocortical afferences. It has been reported recently that the nigrothalamic pathway was activated by nigral DA.‘O In cortical lesioned animals, the disappearance of the frontothalamic pathway could allow the expression of the compensating loop, balancing the partial inactivation of nigrostriatal nals by nigrally released DA.
termi-
Role of the frontai
the two nigrostriatal
cortex on the relationship between dopaminergic pathways
In recent papers ‘vL4 it was proposed that the nigrai increase in the release of DA (produced both by local application of d-amphetamine or contralateral sensorial stimulation) activates the nigrothaiamic pathway and could influence contralateral dopaminergic cells through thalamic structures. Saggital transection of thalamic massa intermedia obliterated the contralateral effect of an increased nigral release of DA, suggesting that some thalamic structures could act as a relay between the two nigrostriatal tracts. Cortical lesions also appear able to induce such obliteration of the contralateral effect of an increased nigral release of DA. Thus cortical pericrutiate cortex can also be considered as a relay structure. However, previous results are not in agreement with such a hypothesis. Lesion of anterior part of the corpus callosum, which interrupts the transversal corticostriatal tract, did not modify the contralateral response of dopaminergic cells to nigral application of d-amphetamine.” Thus, the sensory motor cortex may act through the corticothalamic pathway, serving as a gate control of the interhemispheric linkage between the two parts of the basal ganglia.
REFERENCES
Beaumont K., Maurin Y., Reisine T. D., Fields J. Z., Spokes E., Bird E. D. and Yamamura H. 1. (1979) Huntington’s disease and its animal model: alterations in kainic acid binding. L!fe Sei. 24, 809-816. Blake D. J., Zarzecki P. and Somjen G. G. (1976) Electrophysiolo@cal study of corticocaudate projections in cats. J. Neurobiol. 7, 143-156.
Buchwald N. A., Price D. D., Vernon L. and Hull C. D. (1973) Caudate intracellular response to thalamic and cortical inputs. ExpZ iVeuro1. 38, 31 I-321. Chtramy A., Nieoullon A., Michelot R. and Glowinski J. (1977) Effects of intranigral application of dopamine and substance P on the in oizio release of newly synthesized ‘H-dopamine in the ipsilateral caudate nucleus of the cat. Neurosci Lert. 4, 105-109.
5. ChPramy A., Chesselet M. F., Romo R., Leviel V. and Glowinski J. (1983) Effects of unilateral electrical stimulation of various thalamic nuclei on the release of dopamine from dendrites and nerve terminals of neurons of the two nigrostriatal dopaminergic pathways. Neuroscience 8, 767-780. 6. Chiramv A.. Leviel V.. Daudet F.. Guibert B.. Chesselet M. F. and Glowinski J. (1981) Involvement of the thalamus in the r&iprocai regulation of the two nigrostriatal dopaminergic pathways. ~e~ro.~cjence 6, X57-2668. 7. Garcia-Rill E., Hull C. D., Levine M. S. and Buchwald N. A. (1979) The spontaneous firing patterns of forebrain neurons. IV. Effects of bilateral and unilateral frontal cortical ablations on firing of caudate, globus pallidus and thalamic neurons. Brain Res. 165, 23-36. 8. Garcia-Rill E., Nieto A., Adinolfi A., Hull C. D. and Buchwald N. A. (1979) Projections to the neostriatum from the cat precruciate cortex. Anatomy and physiology. Brain Res. 170, 393407. 9. Groves P. M., Wilson C. J., Young S. J. and Rebec G. N. (1975) Self inhibition by dopaminergic neurones. Science, N.Y. 190, 522. 10. Henke H. and Cuenod M. (1979) t-Glutamate specific ‘H-kainic acid binding in the rat neo striatum after degeneration of the cortico strintal pathway. Neurosci. Letf. 11, 341-345. 11. Hull C. D., Levine M. S., Buchwald N. A., Heller A. and Browning R. A. (1974) The spontaneous firing patterns of forebrain neurons. I. The effects of dopamine and non-dopamine depIeting lesions on caudate unit firing patterns. Bruin Res. 73, 448-460.
12. Jasper H. H. and Ajmone-Marsan C. (1954) A Stereofaxic Atlay of’ the Diencephalon of the Caf. National Research Council of Canada, Ottawa. 13. Leviel V., Chiiramy A. and Glowinski J. (1979) Role of the dendritic release of dopamine in the reciprocal control of the activity of the two nigrostriatal dopaminergic pathways. Nature 280, 236239. 14. Leviel V., Chesselet M. F., Glowinski J. and Chkramy A. (1981) Involvement of the thalamus in the asymetric effects of unilateral sensory stimuli on the two nigrostriatal dopaminergic pathways in the cat. Brain Res. 223, 257-272. 15. Levine M. S., Hull C. D., Buchwaid N. A., Helier A. and Erinoff L. (1977) The spontaneous firing patterns of forebrain neurons: III. Prevention of induced asymmetries in caudate neuronai firing rates by unilaterat thalamic lesions. Bruin Res. 131, 215-225.
16. Nieoullon A.. Chkramy A. and Glowinski J. (1977) Release of dopamine in duo from cat substantia nigra. Nature 266. 375-377.
Cortical control of dopamine release
59
17. Nieoullon A., Chtramy A. and Glowinski J. (1977) Nigral and striatal dopamine release under sensory stimuli. Nafure 269, 34&342. 18. Nieoullon A., Cheramy A. and Glowinski J. (1978) Release of dopamine evoked by electrical stimulation of the motor and visual areas of the cerebral cortex in both caudate nuclei and in the substantia nigra of the cat. Brain Rex 145, 69-83. 19. Nieoullon A., Chtramy A., Leviel V. and Glowinski J. (1979) Effects of the unilateral nigral application of dopaminergic drugs on the in viva release of dopamine in the two caudate nuclei of the cat. Eur. J. Pharmac. 53, 289-296. 20. Ruffieux A. and Schultz W. (1980) Dopaminergic activation of reticulata neurons in the substantia nigra. Nature 285, 240-241. 21. Scatton B., Worms P., Lloyd K. G. and Bartholini G. (1982) Cortical modulation of striatal function. Brain Res. 232, 331-343.
(Accepted 16 February 1984)
NeuroscienceVol. 13, No. 1, pp. 53-59, 1984 Printedin Great Britain
BLOCKADE BY FRONTOCORTICAL LESION OF RECIPROCAL REGULATION BETWEEN THE TWO NIGROSTRIATAL DOPAMINERGIC PATHWAYS V.
LEVIEL, C. KERNY,
C.
BARBERIS,
B.
GUIBERT
and F.
DAUDET
Laboratoire de Physiologie Nerveuse, Dipartement de Neurophysiologie Appliquee, C.N.R.S., 91190 Gif sur Yvette, France
Abstract-Tritiated dopamine synthesized from tritiated tyrosine was estimated simultaneously in the two caudate nuclei and the two substantia nigrae of cats anaesthesized with halothane. In control animals, the electrical stimulation of the right forelimb enhanced dopamine release in the right caudate nucleus and decreased dopamine release in the right substantia nigra. Opposite effects were observed in the contralateral structures. Left nigral application of d-amphetamine produced the same effect. However in cats with extensive lesions of the left pericruciate cortex, an increase in the release of dopamine in the left substantia nigra was the only detectable effect of these two treatments. These results suggest that the cortical structures are involved not only in the transfer of information between the two dopaminergic pathways but are also involved with regulation of the release of dopamine in the striatum originating in the substantia nigra. With regard to the role of the thalamic structures in this transfer of information, it is proposed that the thalamostriatal control of the release of dopamine previously suggested is closely dependent on cortical activity.
functionally linked and similar conclusions resulted from electrophysiological data.” Morphological support of this interhemispheric relationship is not well defined but Levine et al.” and Cheramy et ~1.~concluded that some non-specific thalamic nuclei could act as a fulcrum between the activity of the two nigrostriatal dopaminergic pathways. Cortical structures were also implicated in the regulation of striatal dopamine release, particularly the frontal cortical area. The corticostriatal pathway is well defined by anatomical data and if no part of the striatum is under the sole influence of one functional area of the neocortex, the projections of the sensory motor cortex are the most substantial. In 1978 Nieoullon et ~1.‘~ described a bilateral increase of the release of dopamine in the head of the caudate nucleus in response to electrical stimulation of the sensory motor cortex. More recently Scatton et al.” observed a decrease of DA content in the striatum of rat with lesion of ipsilateral frontal cortex. Electrophysiological data suggest that the cortical input to the striatum is both monosynaptic and facilitatory.2,3 In fact lesion of the frontal cortex produced a marked slowing of caudate neuronal firing.’ Moreover striatocortical inputs are bilateral and there is good evidence for a glutamatergic nature of their neurotransmission.‘.8~‘o Thus in an attempt to test the role of the pericruciate cortical area on the relationship between the two nigrostriatal dopaminergic paths, we examined the effect of a lesion of the sensory motor cortex on two paradigms in which this relation was evidenced:
In 1977 Nieoullon et ~1.‘~ observed a release of dopamine (DA) originating from the dendrites of dopaminergic cells in the substantia nigra. Dopamine, which inhibits the ascending dopaminergic cellq9 was thus considered to be one of the major mechanisms regulating the release of DA in the ipsilateral caudate nucleus. Pharmacologically induced alterations of the release of DA in the substantia nigra resulted consistently in opposite variations of DA release in the striatum.4 Thus, d-amphetamine applied to the substantia nigra through a push-pull cannula superfusing this structure induced a local increase of the release of DA and a decrease in the ipsilateral caudate nucleus, probably due to an inhibition of the dopaminergic cells. However, the simultaneous observation of the release of dopamine in the two caudate nuclei and the two substantia nigrae led Leviel et ~1.‘~ to conclude in 1979 that DA released in the substantia nigra was not acting only on the ipsilateral dopaminergic cells but was able to interfere with contralateral activity of the homologous tract. In fact nigral increase of DA release in one substantia nigra (SN) induced by local application of d-amphetamineI or contralateral sensorial stimulation” resulted not only in a decrease of DA release in the homolateral caudate nucleus (CN) but in an increase in the contralateral CN presumably through a decrease of DA release in the SN. Thus the two nigrostriatal dopaminergic pathways appeared as Abbreviations: CN, caudate nucleus; DA, dopamine; SN, substantia nigra. 53
54
V. Levier ef at.
the nigral application noxious Materials
sensorial
of ~-amphetamine stimulation.
and a non-
EXPERIMENTAL PROCEDURES
L-3,5-[3H]Tyrosine (50 Ci/mM) originated from NEN or Amersham. Halothane was obtained from I.C.I. Pharma (Enghien, France) and d-amphetamine from Cooper (Melun, France). Biological model
Cats, weighting from 2 to 3 kg were used in this study. Under deep (> 3%) halothane anaesthesia, tracheotomy and cannulation of femoral artery was performed. Animals were maintained in the stereotaxic position of a Horsley-Clarke apparatus, (LPC, France) using two bars fixed with screws and acrilyc cement in the occipital and frontal bone. This low pain procedure allowed the maintenance of light anaesthesia with 1.5% halothane during the superfusion. Alveolar COz, arterial blood pressure, electrocardiogram and temperature were recorded during the experiment. Arterial PCO,, POz and pH were also controlled during the experiment. Cortical lesion
Lesions of the left pericruciate cortex were achieved during deep halothane anaesthesia (3.5%) by successive light suctions applied to a maximum depth of 2 mm, and over an area of 4-6 mm2. Lesions affected the superficial part of the anterior and posterior part of the left sigmoidal girus. Histological control of the lesions was performed after each experiment. Depth and extent of the lesions obtained are described in Fig. 1. Imp~an~at~#~0~ Pugh-pull c~~u~ue
quantities found in the six fractions collected just before the treatment was used as an individual control value (lOO~~$. Each successive fraction was then expressed as a percentage of this hasal v&e. Comparisons were made between the means of the values obtained from unlesioned (controls) and lesioned animals. Two-tailed Student’s I test was employed for the statistical analysis. Histological controls
At the end of each experiment, the brain of the cat was perfused with 10% formalin through the carotid artery. Serial frontal sections were stained with cresyl violet: the emplacement of cannulae and the extent of the lesions were then examined (Fig. 1B).
RESULTS
Cortical lesions were made 2 h before the beginning of the superfusion. Compared to controls no alteration of the stability of the release of [-‘HIDA was detected; furthermore the mean of the absolute level of the collected labelled DA did not differ from those obtained from control cats (about 300 pCi in SN and 55OpCi in CN). Thus the cortical lesions did not affect, in these conditions, the spontaneous release of the newly synthesized DA from the nerve terminals of the caudate nuclei or from the dendrites of the substantia nigrae.
Four push-pull cannulae were stereotaxically implanted in the two caudate nuclei (CN) and the two substantia nigrae (SN); coordinates: CN: A = 16, L = 4.5, H = 5 and SN: A = 4, L = 4.5, H = - 5 (from atlas of Jasper and Ajmone-Marsan”). For the positioning of the nigral cannulae, bipolar concentric electrodes were substituted in the mandrels of the nigral cannulae. Lemniscal and nigral electrophysiological responses evoked by electrical stimulations of the contralateral forepaw were then recorded until the tip of the electrode reached the desired structure. Supecfusion procedure and biochemical analysis
The four push-pull cannulae were continuously supplied with artificial ~rebrospinal fluid (in mM: NaCl, 126.5; NaHCO,, 27.5; KCI, 2.i; KH,PC),, 0.5; CaC&, I .l: MgC&, 0.80: NaSO,. 0.5: elucose. 5.9). adjusted to OH 7.3 with 0,-&O, ?9S/? v/vj kixture, aid cintaining
From each cannula and each animal the mean of [‘HIDA
TME
cm”,
Fig. 2. Effects of cortical lesion on the DA release alterations during right forelimb stimulation. [‘H]Dopamine was estimated in 10 min-successive superfusate fractions, collected simuItaneously from the four implanted push-pull cannulae supplied with L-3,5-~3H]tyros~ne in artificial cerebrospinal fluid. The paw of the right forelimb was stimulated for the 10 min of the seventh fraction (square pulses, 0.5 ms, 0.2 Hz. 2-3 V). a, controls; A, lesioned animals. In each animal and for each cannula, [3H]DA in each successive fraction was expressed as a percentage of an average spontaneous release calculated from the six fractions collected before the stimulation. Data are the mean + SEM of results obtained with n animals. (n = 7 for controls. n = 8 for lesioned cats.) *P < 0.05 when compared with corresponding controls values obtained in unlesioned animals. L, left; R, right.
B
_
Fig. 1. Extent of the pericruciate cortical lesion. (A) Schematic drawing showing the extent of damage (darkened area) after removal of the pericruciate cortex. (B) Vertical section of a lesioned animal showing depth of cortical lesion.
55
57
Cortical control of dopamine release Eflects of right sensory stimulation on lesioned animals
(Fig. 2) In control cats electrical stimulations of the right forelimb induced asymmetric changes in the release of i3HfDA from the two caudate nuclei and the two substantia nigrae: the stimulation induced an enhancement of the release from the ipsilateral caudate nucleus linked to a decrease in the corresponding substantia nigra. An opposite alteration appeared in the contralateral side with a decreased release of DA from the caudate nucleus probably due to an increase in the substantia nigra. In cats whose left pericruciate cortex had been lesioned, electrical stimulation of the right forelimb induced an increase in the [3H]DA released in the contralateral substantia nigra: this increase did not differ from the increase which had been obtained in the unlesioned cats. However, no effect of the sensory stimulation was detected in the three other structures, where the level of the spontaneous DA release stayed stable. Efsects of left nigral application of d-amphetamine on iesioned cats (Fig. 3)
~-Amphetamine, applied for 10min in the left substantia nigra of control cats, induced asymmetric changes in the four structures: the release of [3H]DA was enhanced locally in the left SN, but reduced in the ipsilateral CN, and opposite changes were observed in contralateral structures. In cortically le-
-w7.’ ..J
30
80
80
120
Fig. 3. Effects of cortical lesion on the DA release alterations during nigral appli~tion of ~-amphetamine. Experiments
were carried out as described in Fig. 2. d-Amphetamine was applied for the 10min of the seventh fraction. n , controls; A. lesioned animals, *, P i 0.05 when values obtained from lesioned animals (n = ?) were compared with corresponding control values obtained from unlesioned animals (n = 7). L, left; R, right.
sioned cats, d-amphetamine still produced a sharp increase of the release of DA in the left SN, but in spite of this important variation, the release of DA was not reduced in the ipsilateral CN. Furthermore the s~ntaneous release of DA was not affected in the contralateral structures after this nigral application of d-amphetamine in contrast to the effect in unlesioned animals. DISCUSSION
These results show that a lesion of the pericruciate cortex is without effect on the alteration of DA release in the SN produced by local application of d-amphetamine or contralateral forepaw stimulation. However, after such a lesion, this increase of the DA release in the SN is unable to induce either an ipsilateral decrease in the striatum or a contralateral expected increase. Furthermore the spontaneous release of DA in the contralateral SN was unchanged. These observations enphasise the major role played by the frontal cortex in regulating the release of DA in the extrapyramidal system. Role of the pericruciate cortex on the tonicai refease of dopamine
Surprisingly, the cortical lesion seems to have no effect on the tonic release of DA in the two caudate nuclei. In 1978 Nieoullon et al.” have shown, using a similar model, that electrical stimulation of the sensory motor cortex resulted in an increase of DA release in the two caudate nuclei. From this observation, these authors extended the excitatory role generally attributed to the corticostriate pathway onto the dopaminergic terminals. Thus, cortical lesion should result in a decreased release of dopamine in the striatum. However, we did not observe such a decrease, since the mean value of [3H]DA released every 10 min was not different from the mean value obtained in non-lesioned animals. This fact is not paradoxical for two reasons: first, the cortical lesions in our model were always performed 2 or 3 h before the beginning of the superfusion and this time should be sufficient to compensate for a putative decrease in the striatal release of dopamine. Second, the corticostriatal influence could be only an excitatory mechanism, not responsible for tonic release of DA in the striatum. The pericruciate cortex and alterations of the release of dopamine in the striatum
Paradoxically, after cortical lesion, we do not see a decrease of DA release in the striatum in spite of the increase in DA in the ipsilateral SN. The inhibitory action of DA on the nigrostriatal cells should result in such an alteration. Furthermore, contralateral sensorial stimulation also produce a nigral increase of the release of DA without affecting the
V. Leviel et al
58
corresponding striatal DA release. Similar observations have already been made, using the same biological model.‘-14 An increased release of DA in the substantia nigra induced by sensorial stimulation14 or local application of d( +)-amphetamine6 was without effect on the release of DA in the ipsilateral caudate nucleus on cats whose massa intermedia of the thalamus were sectioned. These results led the authors to propose the existence of a nigrothalamostriatal mechanism able to compensate for the inhibiton of the nigrostriatal cells induced by nigral DA. This compensatory mechanism may be under control of an uncharacterized thalamic relay. In fact, electrical stimulation of various thalamic nuclei has been shown to alter the release of DA in both the caudate nuclei and substantia nigrae.’ The proposed compensatory mechanism might be activated by way of the DA sensitive nigrothalamic tract, and normally inhibited at the thalamic level by frontocortical afferences. It has been reported recently that the nigrothalamic pathway was activated by nigral DA.‘O In cortical lesioned animals, the disappearance of the frontothalamic pathway could allow the expression of the compensating loop, balancing the partial inactivation of nigrostriatal nals by nigrally released DA.
termi-
Role of the frontai
the two nigrostriatal
cortex on the relationship between dopaminergic pathways
In recent papers ‘vL4 it was proposed that the nigrai increase in the release of DA (produced both by local application of d-amphetamine or contralateral sensorial stimulation) activates the nigrothaiamic pathway and could influence contralateral dopaminergic cells through thalamic structures. Saggital transection of thalamic massa intermedia obliterated the contralateral effect of an increased nigral release of DA, suggesting that some thalamic structures could act as a relay between the two nigrostriatal tracts. Cortical lesions also appear able to induce such obliteration of the contralateral effect of an increased nigral release of DA. Thus cortical pericrutiate cortex can also be considered as a relay structure. However, previous results are not in agreement with such a hypothesis. Lesion of anterior part of the corpus callosum, which interrupts the transversal corticostriatal tract, did not modify the contralateral response of dopaminergic cells to nigral application of d-amphetamine.” Thus, the sensory motor cortex may act through the corticothalamic pathway, serving as a gate control of the interhemispheric linkage between the two parts of the basal ganglia.
REFERENCES
Beaumont K., Maurin Y., Reisine T. D., Fields J. Z., Spokes E., Bird E. D. and Yamamura H. 1. (1979) Huntington’s disease and its animal model: alterations in kainic acid binding. L!fe Sei. 24, 809-816. Blake D. J., Zarzecki P. and Somjen G. G. (1976) Electrophysiolo@cal study of corticocaudate projections in cats. J. Neurobiol. 7, 143-156.
Buchwald N. A., Price D. D., Vernon L. and Hull C. D. (1973) Caudate intracellular response to thalamic and cortical inputs. ExpZ iVeuro1. 38, 31 I-321. Chtramy A., Nieoullon A., Michelot R. and Glowinski J. (1977) Effects of intranigral application of dopamine and substance P on the in oizio release of newly synthesized ‘H-dopamine in the ipsilateral caudate nucleus of the cat. Neurosci Lert. 4, 105-109.
5. ChPramy A., Chesselet M. F., Romo R., Leviel V. and Glowinski J. (1983) Effects of unilateral electrical stimulation of various thalamic nuclei on the release of dopamine from dendrites and nerve terminals of neurons of the two nigrostriatal dopaminergic pathways. Neuroscience 8, 767-780. 6. Chiramv A.. Leviel V.. Daudet F.. Guibert B.. Chesselet M. F. and Glowinski J. (1981) Involvement of the thalamus in the r&iprocai regulation of the two nigrostriatal dopaminergic pathways. ~e~ro.~cjence 6, X57-2668. 7. Garcia-Rill E., Hull C. D., Levine M. S. and Buchwald N. A. (1979) The spontaneous firing patterns of forebrain neurons. IV. Effects of bilateral and unilateral frontal cortical ablations on firing of caudate, globus pallidus and thalamic neurons. Brain Res. 165, 23-36. 8. Garcia-Rill E., Nieto A., Adinolfi A., Hull C. D. and Buchwald N. A. (1979) Projections to the neostriatum from the cat precruciate cortex. Anatomy and physiology. Brain Res. 170, 393407. 9. Groves P. M., Wilson C. J., Young S. J. and Rebec G. N. (1975) Self inhibition by dopaminergic neurones. Science, N.Y. 190, 522. 10. Henke H. and Cuenod M. (1979) t-Glutamate specific ‘H-kainic acid binding in the rat neo striatum after degeneration of the cortico strintal pathway. Neurosci. Letf. 11, 341-345. 11. Hull C. D., Levine M. S., Buchwald N. A., Heller A. and Browning R. A. (1974) The spontaneous firing patterns of forebrain neurons. I. The effects of dopamine and non-dopamine depIeting lesions on caudate unit firing patterns. Bruin Res. 73, 448-460.
12. Jasper H. H. and Ajmone-Marsan C. (1954) A Stereofaxic Atlay of’ the Diencephalon of the Caf. National Research Council of Canada, Ottawa. 13. Leviel V., Chiiramy A. and Glowinski J. (1979) Role of the dendritic release of dopamine in the reciprocal control of the activity of the two nigrostriatal dopaminergic pathways. Nature 280, 236239. 14. Leviel V., Chesselet M. F., Glowinski J. and Chkramy A. (1981) Involvement of the thalamus in the asymetric effects of unilateral sensory stimuli on the two nigrostriatal dopaminergic pathways in the cat. Brain Res. 223, 257-272. 15. Levine M. S., Hull C. D., Buchwaid N. A., Helier A. and Erinoff L. (1977) The spontaneous firing patterns of forebrain neurons: III. Prevention of induced asymmetries in caudate neuronai firing rates by unilaterat thalamic lesions. Bruin Res. 131, 215-225.
16. Nieoullon A.. Chkramy A. and Glowinski J. (1977) Release of dopamine in duo from cat substantia nigra. Nature 266. 375-377.
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17. Nieoullon A., Chtramy A. and Glowinski J. (1977) Nigral and striatal dopamine release under sensory stimuli. Nafure 269, 34&342. 18. Nieoullon A., Cheramy A. and Glowinski J. (1978) Release of dopamine evoked by electrical stimulation of the motor and visual areas of the cerebral cortex in both caudate nuclei and in the substantia nigra of the cat. Brain Rex 145, 69-83. 19. Nieoullon A., Chtramy A., Leviel V. and Glowinski J. (1979) Effects of the unilateral nigral application of dopaminergic drugs on the in viva release of dopamine in the two caudate nuclei of the cat. Eur. J. Pharmac. 53, 289-296. 20. Ruffieux A. and Schultz W. (1980) Dopaminergic activation of reticulata neurons in the substantia nigra. Nature 285, 240-241. 21. Scatton B., Worms P., Lloyd K. G. and Bartholini G. (1982) Cortical modulation of striatal function. Brain Res. 232, 331-343.
(Accepted 16 February 1984)