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Contains fulltext : 79555.pdf (Publisher’s version ) (Closed access) Mesolimbic beta-, but not alpha-adrenoceptors control the accumbal release of dopamine that is derived from alpha-methyl-para-tyrosine-sensitive pools of newly synthesized neurotransmitter. The aim of this study was to investigate which of these adrenoceptors control the accumbal release of dopamine that is derived from reserpine-sensitive pools of previously stored neurotransmitter. Rats, that were divided in low-responders and high-responders to novelty, were pretreated with 1 mg/kg of reserpine before the alpha-adrenergic-agent phentolamine or the beta-adrenergic-agent isoproterenol was locally applied into the nucleus accumbens. The original finding that phentolamine and isoproterenol increased accumbal dopamine levels in low-responders and high-responders was replicated. Reserpine reduced the phentolamine-induced increase of accumbal dopamine in both types of rat. However, phentolamine could still increase accumbal dopamine levels in reserpine-treated high-responders, but not anymore in reserpine-treated low-responders. Reserpine did not reduce the isoproterenol-induced increase of accumbal dopamine in any type of rat. This study demonstrates that mesolimbic alpha-, but not beta-adrenoceptors control the accumbal release of dopamine that is derived from reserpine-sensitive storage vesicles. In addition, these data confirm our previous finding that dopamine can still be released from storage vesicles of reserpinized high-responders, but not of reserpinized low-responders. The collected data underline our notion that alpha- and beta-adrenergic drugs may have therapeutic effects in patients suffering from diseases in which accumbal dopamine is involved.

Contains fulltext : 80658.pdf (Publisher’s version ) (Closed access) The role of GABA(A) receptors in the mediodorsal thalamus (mdT) in turning behaviour of rats was studied. Neither the GABA(A) receptor agonist muscimol (50 ng) nor the antagonist bicuculline (200 ng) unilaterally injected into the mdT elicited any behavioural change. Unilateral injection of the acetylcholine receptor agonist (carbachol, 5 microg) into the nucleus accumbens shell has been found to elicit contraversive circling while unilateral injection of a mixture of dopamine D(1) ((+/-)-1-phenyl-2,3,4,5-tetrahydro-1H-3-benzazepine-7,8-diol [SKF 38393], 5 microg) and D(2) (quinpirole, 10 microg) receptor agonists into the same site is known to elicit contraversive pivoting. The contraversive circling induced by unilateral injection of carbachol (5 microg) into the nucleus accumbens shell was dose-dependently inhibited by muscimol (25 and 50 ng) injected into the mdT. This inhibitory effect of muscimol (50 ng) was antagonised by co-administration of bicuculline (200 ng), which alone did not modify the contraversive circling induced by carbachol (5 microg). The contraversive pivoting induced by unilateral injection of a mixture of SKF 38393 (5 microg) and quinpirole (10 microg) into the nucleus accumbens shell was inhibited by muscimol (25 and 50 ng) injected into the mdT, whereas bicuculline (200 ng) injected into the mdT did not significantly modify the pivoting. The inhibitory effect of muscimol (50 ng) on the pivoting induced by a mixture of SKF 38393 (5 microg) and quinpirole (10 microg) was not dose-dependent and not antagonised by bicuculline (200 ng). The present study suggests that GABA(A) receptors in the mdT play a limited role in spontaneously occurring locomotor activity. Secondly, this study demonstrates that GABA(A) receptors in the mdT transmit accumbens-dependent cholinergic circling, but not accumbens-dependent dopaminergic pivoting, to other brain structures. Finally, the present study shows that muscimol-sensitive, non-GABA(A) receptors in the mdT influence the accumbens-dependent dopaminergic pivoting. To what extent GABA(B) receptors in the mdT mediate the muscimol-induced effects upon the dopaminergic pivoting behaviour requires additional research.

Contains fulltext : 49115.pdf (Publisher’s version ) (Closed access) Systemic administration of high doses of dexamphetamine induces a dopamine efflux that has its intracellular origin in both the vesicular, reserpine-sensitive dopamine pool and the cytosolic, alpha-methyl-para-tyrosine-sensitive, newly synthesized dopamine pool. It remains unknown whether locally administered dexamphetamine produces similar effects. Using a brain microdialysis technique that is combined with a microinjection needle, the contribution of the vesicular and cytosolic pools to the dopamine efflux induced by striatal injection of dexamphetamine was analyzed in rats. The transient striatal dopamine efflux induced by intrastriatal injection of dexamphetamine (1.0 microg/0.5 microl) was significantly reduced by systemic administration of reserpine (5mg/kg i.p., given 24 h earlier) or alpha-methyl-para-tyrosine (250 mg/kg i.p., given 2 h earlier). The effects of dexamphetamine on the striatal dopamine were nearly nullified by combined treatment with reserpine and alpha-methyl-para-tyrosine. The sum of the amounts of extracellular dopamine that was sensitive to either reserpine or alpha-methyl-para-tyrosine, was far greater than 100%, namely 146.1% of the basal dopamine level and 144.0% of the dexamphetamine-induced dopamine level. The present study indicates that both the vesicular dopamine pool and the cytosolic dopamine pool contribute to the transient increase of striatal dopamine efflux induced by intrastriatal injection of dexamphetamine. This study also suggests that striatally applied dexamphetamine can promote the redistribution of rat striatal dopamine from vesicles to the cytosol in vivo.

Contains fulltext : 58401.pdf (Publisher’s version ) (Closed access) The role of GABA(A) receptors in the pedunculopontine tegmental nucleus in turning behaviour of rats was studied. Unilateral injection of the GABA(A) receptor agonist, muscimol (25-100 ng), into the pedunculopontine tegmental nucleus dose-dependently produced contraversive pivoting, namely tight head-to-tail turning marked by abnormal hindlimb backward stepping. This effect was GABA(A) receptor specific, since it was prevented by the GABA(A) receptor antagonist, bicuculline (50 ng), which alone did not elicit turning behaviour. Unilateral injection of a mixture of dopamine D(1) ((+/-)-1-phenyl-2,3,4,5-tetrahydro-1H-3-benzazepine-7,8-diol [SKF 38393], 5 microg) and D(2) (quinpirole, 10 microg) receptor agonists into the nucleus accumbens shell has been found to elicit contraversive pivoting, whilst unilateral injection of the acetylcholine receptor agonist (carbachol, 5 microg) into the same site is known to elicit contraversive circling, namely turning marked by normal stepping. The pivoting induced by a mixture of SKF 38393 (5 microg) and quinpirole (10 microg) injected into the nucleus accumbens shell was significantly inhibited by bicuculline (50 ng) injected into the pedunculopontine tegmental nucleus, whereas muscimol (25 ng) had no effect. Neither muscimol (25 ng) nor bicuculline (50 ng) modulated the contraversive circling induced by carbachol (5 microg) injected into the nucleus accumbens shell. It is therefore concluded that unilateral stimulation of GABA(A) receptors in the pedunculopontine tegmental nucleus can elicit contraversive pivoting and that the pedunculopontine tegmental nucleus is one of the output stations of the accumbens region that mediates shell-specific, dopaminergic pivoting, but not of the accumbens region that mediates shell-specific, cholinergic circling.

The main goal of this study was to provide in vivo neurochemical evidence that mesolimbic alpha- and beta-adrenoceptors direct the release of mesolimbic dopamine. Both high responders to novelty and low responders to novelty were used to study the effects of intra-accumbal administered adrenergic agents on the dopamine release in the nucleus accumbens during two conditions, namely at rest (non-challenge) and when exposed to a "new cage" (challenge). Under non-challenged condition: phenylephrine (alpha-adrenergic agonist) induced a dose-dependent increase in dopamine release that was significantly larger in high responders; phentolamine (alpha-adrenoceptor antagonist) also induced a dose-dependent increase in dopamine that was significantly larger in low responders; isoproterenol (beta-adrenoceptor agonist) induced a dose-dependent increase in dopamine that did not differ between the two types of rat; propranolol (beta-adrenoceptor antagonist) did not change the dopamine release. Under challenged condition: phenylephrine and phentolamine both increased dopamine release without type-specific differences; only in low responders did isoproterenol increase the novelty-induced dopamine release; only in high responders did propranolol decrease the novelty-induced dopamine release. The in vivo neurochemical data are discussed in view of the outcome of earlier reported in vitro studies and pharmaco-behavioral studies. Overall the data reveal that mesolimbic noradrenaline has a dual role in the nucleus accumbens. It is argued that stimulation of alpha-adrenoceptors and beta-adrenoceptors, located postsynaptically on dopamine nerve-endings, inhibits and facilitates, respectively, dopamine release, whereas stimulation of presynaptic alpha-adrenoceptors inhibits the release of noradrenaline and, subsequently, disinhibits the release of dopamine. Moreover, it is argued that non-challenged high responders have a relatively low (alpha/beta) noradrenergic tonus that changes into a relatively high (alpha/beta) noradrenergic tonus during challenge, and that non-challenged low responders have a relatively high (alpha) adrenergic tonus that changes into a relatively low (alpha) noradrenergic tonus during challenge. In general, the present data clearly reveal that both alpha- and beta-adrenoceptors differentially regulate dopamine release in the nucleus accumbens. This regulation is individual-specific and depends on the test-condition (challenged versus non-challenged).

Item does not contain fulltext The purpose of the present study was two-fold: (i) to investigate to what extent novelty, i.e. a novel cage with slightly larger dimensions than the home cage and lacking the floor covering that was originally present, produced behavioural effects in high responders to novelty and low responders to novelty that could be correlated with the extracellular amount of accumbal dopamine, using the microdialysis technique, and (ii) to establish the ability of the catecholamine synthesis inhibitor a-methyl-p-tyrosine to inhibit the novelty-induced responses in high and low responders.The difference in the behavioural response to novelty between the high and low responders was limited to walking, which lasted significantly longer in high responders than in low responders. The novelty-induced increase in extracellular concentration of accumbal dopamine was significantly greater in high responders than in low responders; moreover, the shape of the growth curves differed between high and low responders. The behavioural changes did not correlate with the neurochemical effects, which outlasted the duration of the novelty-induced behavioural arousal. It is hypothesized that this long-lasting increase in accumbal dopamine produces "adaptive changes" that help and/or allow the animal to incorporate knowledge about the condition that it experienced. When the nucleus accumbens was perfused with a-methyl-p-tyrosine for a period of 40 min, given at the same time as the transfer of the rat to the novel cage, it reduced the novelty-induced increase in walking in the high responders, but did not alter the novelty-induced behaviour of low responders. Finally, a-methyl-p-tyrosine reduced the novelty-induced increase in the release of accumbal dopamine in high responders, but enhanced it in low responders. The present neurochemical data are discussed in view of the outcome of earlier reported pharmaco-behavioural studies on the neurochemical state of the nucleus accumbens of non-challenged versus challenged high and low responders. It is hypothesized that, in the high responder, exposure to novelty enhances the release of accumbal dopamine from reserpine-resistant, a-methyl-p-tyrosine-sensitive pools that are under the stimulatory control of B-adrenergic receptors in the nucleus accumbens, and that, in the low responder, exposure to novelty enhances the release of accumbal dopamaine from reserpine-sensitive, a-methyl-p-tyrosine-resistant pools that are under the inhibitory control of a-adrenergic receptors in the nucleus accumbens.

Item does not contain fulltext The goal of the present study was to establish the behavioral role of the nucleus accumbens (Nacc) core in the feed-forward spiraling striato-nigro-striatal circuitry that transmits information from the Nacc shell toward the dorsal subregion of the neostriatum (DS) in freely moving rats. Unilateral injection of mu-opioid receptor agonist [D-Ala(2),N-Me-Phe(4),Gly(5)-ol]-enkephalin (DAMGO; 1 and 2mug), but not the delta1-opioid receptor agonist [D-Pen(2,5)]-enkephalin (4mug) or the delta2-opioid receptor agonist [D-Ala(2),Glu(4)]-deltorphin (2mug), into the ventral tegmental area (VTA) produced contraversive circling in a dose-dependent manner. The effect of DAMGO was mu-opioid receptor-specific, because the mu-opioid receptor antagonist D-Phe-Cys-Tyr-D-Trp-Orn-Thr-Phe-Thr-NH2 (0.1 and 1mug), which alone did not elicit any turning behavior, dose-dependently inhibited the effect of DAMGO. Injection of the dopamine D1/D2 receptor antagonist cis-(Z)-flupentixol (1 and 10mug) into the Nacc shell ipsilaterally to the VTA significantly inhibited DAMGO (2mug)-induced circling. Similar injections of cis-(Z)-flupentixol into the Nacc core inhibited DAMGO-induced circling, but, in addition, replaced circling by pivoting, namely turning behavior during which the rat rotates around its disfunctioning hindlimb. The present findings show that unilateral stimulation of mu-, but not delta-, opioid receptors in the VTA elicits contraversive circling that requires a relatively hyperdopaminergic activity in both the shell and the core of the Nacc at the opioid-stimulated side of the brain. The Nacc core plays an essential role in the transmission of information directing the display of pivoting that is elicited by an increased dopaminergic activity in the Nacc shell. It is concluded that the Nacc core is an essential link in the feed-forward spiraling striato-nigro-striatal circuitry that transmits information from the Nacc shell toward the DS in freely moving rats.

The prefrontal cortex has often been implicated in the pathophysiology of schizophrenia. Schizophrenic patients are known to suffer from certain information processing deficits, which can be detected, among others, in the prepulse inhibition and the latent inhibition paradigm. The present study was designed to investigate the role of dopamine receptors in the medial prefrontal cortex in prepulse inhibition and latent inhibition. The results show that the local application of the selective antagonist of the dopamine D1-like receptor family, SCH 39166, into the medial prefrontal cortex dose-dependently reduced prepulse inhibition. Likewise, the selective antagonist of the dopamine D2-like receptor family, sulpiride, injected into the medial prefrontal cortex dose-dependently reduced prepulse inhibition. Neither of these antagonists, however, influenced latent inhibition as measured with the conditioned taste aversion paradigm. These data further indicate that the neuronal substrates of latent inhibition and prepulse inhibition are clearly different. Since the prefrontal cortex is intimately related to subcortical dopamine, the possible differential involvement of subcortical dopaminergic terminal fields in prepulse inhibition and latent inhibition is discussed.

The present study was carried out to investigate the role of corticosteroids in the dexamphetamine-induced sensitization of the mesolimbic, noradrenergic system. The experimental design of adrenalectomy and hormone replacement was chosen for exploration of this question. The dexamphetamine-induced sensitization of mesolimbic, alpha 1 adrenergic receptors in the ventral striatum was studied by administering intra-accumbens injections of the alpha 1 agonist, phenylephrine (10 micrograms), given 24 h after a priming injection of intra-accumbens administered dexamphetamine (10 micrograms), which itself elicits an increase in locomotor activity. In this paradigm phenylephrine produces an increase in locomotor activity, an effect which does not occur in rats which are not sensitized by dexamphetamine. Adrenalectomy produced a slight, but significant, attenuation of the response to the priming injections of dexamphetamine. Replacement treatments (500 micrograms/kg per drug) with corticosterone or deoxycorticosterone, agents which preferentially bind with mineralocorticoid receptors, did not affect the dexamphetamine response, whereas replacement treatment with dexamethasone, which preferentially binds with glucocorticoid receptors, strongly potentiated this response. In view of the fact that the adrenalectomy-induced fall in corticosteroids can produce an up-regulation of glucocorticoid receptors, but not mineralocorticoid receptors, these data led to the conclusion that glucocorticoid receptors which are present in the cell bodies of noradrenergic, serotonergic and dopaminergic neurons are critical for the dexamphetamine response in drug-naive rats. The phenylephrine response was also strongly enhanced in adrenalectomized rats treated with dexamethasone. Since the magnitude of the dexamphetamine response is known to determine the magnitude of the phenylephrine response, the role of glucocorticoid receptors in the dexamphetamine-induced sensitization of the phenylephrine response remains to be established. Conversely, adrenalectomy nearly completely abolished the dexamphetamine-induced sensitization of the phenylephrine response. The latter response was reinstated by replacement treatment with corticosterone or deoxycorticosterone. These data show that mineralocorticoid receptors, which are present among others in the ventral striatum, are critical for the dexamphetamine-induced sensitization of mesolimbic, alpha 1 adrenergic receptors in the ventral striatum. The present study opens the perspective that secretion of corticosteroids in response to stressful stimuli--be it pharmacological or environmental--is the key to the question of why dexamphetamine and environmental challenges are interchangeable in the development of sensitization of mesolimbic, alpha 1 adrenergic receptors.

Enkephalin immunoreactivity is used to divide the feline substantia innominata into circumscript subregions, i.e. the “striatopallidal system” and the “extended amygdala”. In addition, enkephalin immunoreactivity is used to subdivide the striatopallidal system into two distinct areas, i.e. the subcommissural part of the globus pallidus displaying high enkephalin immunoreactivity and the ventral pallidum displaying moderate enkephalin immunoreactivity. The anterograde axonal transport of Phaseolus vulgaris -leucoagglutinin is used to study the efferents of these areas innervating the caudate nucleus and the nucleus accumbens. It is found that the enkephalin-immunoreactive subcommissural part of the globus pallidus as well as the dorsal enkephalin-immunoreactive regions of the extended amygdala project topographically along a rostrocaudal and mediolateral dimension to the nucleus accumbens. The far rostral parts of the caudate nucleus are found to be innervated by the subcommissural part of the globus pallidus whereas the extended amygdala has no such connection. This pathway is also found to be topographically organized along a mediolateral dimension. The non-enkephalin-immunoreactive area ventral and lateral to the subcommissural part of the globus pallidus is found to have no projections to the nucleus accumbens and caudate nucleus. This region rather innervates the olfactory tubercle. In contrast to the striatopallidal system the sublenticular part of the extended amygdala preferentially projects to the adjoining part of the extended amygdala, i.e. the bed nucleus of the stria terminalis. However, the ventral regions preferentially innervate the medial division of the bed nucleus of the stria terminalis whereas the dorsal regions preferentially innervate the lateral division of the bed nucleus of the stria terminalis. These data indicate that the differential forebrain systems represented in the feline substantia innominata, i.e. the striatopallidal system and extended amygdala have differential output stations. The results are discussed in view of the role of the subcommissural part of the globus pallidus and the nucleus aecumbens in orofacial dyskinesia and schizophrenia, respectively.

Contains fulltext : 48517.pdf (Publisher’s version ) (Closed access) The activation of the delta-opioid receptors in the nucleus accumbens is known to induce a large and rapid increase of accumbal dopamine efflux. (+/-)-TAN-67 (2-methyl-4a(alpha)-(3-hydroxyphenyl)-1,2,3,4,4a,5,12,12a(alpha)-octahydro -quinolino[2,3,3,-g]isoquinoline) is a centrally acting non-peptidic delta opioid receptor agent which has recently become available. Interestingly, the (+) enantiomer of TAN-67 induces hyperalgesia in contrast to the (-) enantiomer of TAN-67 that produces profound antinociceptive effects in mice; the latter effects are mediated through delta-1 receptor stimulation. Using the microdialysis technique, the ability of the enantiomers of TAN-67 to alter the release of accumbal dopamine in vivo was analyzed. Like the 25-min infusion of the selective delta-1 opioid receptor agonist (D-[Pen2,5]-enkephalin) DPDPE (50 nM) and the delta-2 opioid receptor agonist deltorphin II (50 nM), the 25-min infusion of both (-)-TAN-67 (25 and 50 nM) and (+)-TAN-67 (25 and 50 nM) into the nucleus accumbens produced a similar transient dose-dependent increase in the accumbal extracellular dopamine level. Naloxone (1 mg/kg i.p., given 25 min prior to the drugs), namely a treatment that is known to inhibit the increase of dopamine induced by DPDPE and deltorphin II, did not affect the transient increase in the accumbal dopamine level produced by infusion of the enantiomers of TAN-67. The DPDPE and deltorphin II-induced increase in accumbal dopamine level, but not that of (-)-TAN-67 and (+)-TAN-67, was eliminated by subsequently perfused tetrodotoxin (2 microM) into the nucleus accumbens. The increase in accumbal dopamine level produced by an infusion of (-)-TAN-67 and (+)-TAN-67 was not altered by a Ca2+-free Ringer's solution. The (-)-TAN-67 and (+)-TAN-67-induced accumbal dopamine efflux was strongly prevented by reserpine (5 mg/kg i.p., given 24 h earlier) or alpha-methyl-para-tyrosine (250 mg/kg i.p., given 2 h earlier). The effects of the enantiomers of TAN-67 on the accumbal dopamine were nullified by combined treatment with reserpine and alpha-methyl-para-tyrosine. The (-)-TAN-induced dopamine efflux was significantly reduced by the N-methyl-D-aspartate (NMDA) receptor antagonists ifenprodil (20 mg/kg i.p., 20 min before) and MK-801 (0.5 mg/kg i.p., 20 min before), respectively. The effects of (-)-TAN-67 on the dopamine efflux were also inhibited by the free radical scavenger N-2-mercaptopropionyl glycine (100 mg/kg i.p., 20 min before). These results show that both enantiomers of TAN-67 enhance the release of reserpine sensitive, vesicular dopamine and alpha-methyl-p-tyrosine sensitive, cytosolic dopamine from dopaminergic nerve terminals in the nucleus accumbens in a way that is independent of neural activity; activation of delta opioid receptors plays no role in these events. All together, the results suggest that (-)-TAN-67 can generate a burst of free radicals that in turn trigger a release of glutamate that ultimately via activation of NMDA receptors enhances the release of dopamine from dopaminergic nerve terminals in the nucleus accumbens.

It has been shown that orofacial dyskinesia, i.e. a syndrome of abnormal involuntary movements of the facial muscles, can be elicited from the sub-commissural part of the globus pallidus and the adjoining dorsal parts of the extended amygdala in cats. Until now it is unknown whether the peripeduncular nucleus, which receives input from these structures according to anterograde tracing studies, plays a role in the funneling of orofacial dyskinesia to lower output stations. In the present study the connection of the subcommissural part of the globus pallidus and dorsal parts of the extended amygdala with the peripeduncular nucleus was investigated anatomically, using cholera toxin subunit B as a retrograde tracer, and functionally, using intracerebral injections of GABAergic compounds. The anatomical data show that the sub-commissural part of the globus pallidus and dorsal parts of the extended amygdala were marked by cholera toxin sub-unit B-immunoreactive cells following injections of this retrograde tracer into the peripeduncular nucleus. Thus, it could be confirmed that the peripeduncular nucleus receives input from the sub-commissural part of the globus pallidus and dorsal parts of the extended amygdala. Still, the orofacial dyskinesia elicited by local injections of the GABA antagonist picrotoxin (500 ng/0.5 ml) into the sub-commissural part of the globus pallidus and dorsal extended amygdala was only in part attenuated by local injections of the GABA agonist muscimol (100 ng/l ml) into the peripeduncular nucleus. Only the number of tongue protrusions was significantly attenuated, but not that of the ear and cheek movements. Furthermore, tongue protrusions, but no additional oral movements, were elicited by picrotoxin injections (375–500 ng) into the peripeduncular nucleus. However, these effects were dose dependent and could only be elicited from the dorsal parts of the peripeduncular nucleus. Injections into the ventral parts of the extended amygdala were ineffective in every respect in the present investigation. The data show that the peripeduncular nucleus does not funnel the orofacial dyskinesia from the sub-commissural part of the globus pallidus and dorsal parts of the extended amygdala to lower brain structures despite the fact that it is innervated by the former regions. The finding that the peripeduncular nucleus itself is only involved in the modulation of the display of tongue protrusions may explain why manipulations with the peripeduncular nucleus only affected this aspect of the orofacial dyskinesia elicited from the sub-commissural part of the globus pallidus and dorsal parts of the extended amygdala.

The acute behavioural and metabolic consequences of functional changes following unilateral intracaudate kainic acid at the level of the feline caudate nucleus, the substantia nigra pars reticulata and the deeper layers of the colliculus superior were investigated. The present study became possible since it was previously found that unilateral changes in neurotransmission processes in these structures all result in behavioural alterations that can be distinguished from each other. During the first 17 min after kainic acid, all animals displayed contralateral forced staccato head turning; these movements are characteristic for an activation of dopamine receptors and/or inhibition of GABA receptors in the rostromedial caudate nucleus. Between 15 and 50 min, all animals displayed fast, uninterrupted contralateral forced head, torso or body turning; these movements are characteristic for an activation of nigral GABA receptors. From about 48 min, all animals displayed sequences of short contralateral forced ear, head, torso and body turnings; these movements are characteristic for an inhibition of collicular GABA receptors. Furthermore, most cats displayed ipsilateral orofacial dyskinetic movements during the whole 180 min observation period. Metabolism was analysed in three cats that received [14C]2- d -deoxyglucose immediately before, 5 min after, or 70 min after kainic acid. Metabolism was increased in the ipsilateral caudate nucleus; this effect was most pronounced in the cat that received deoxyglucose immediately before kainic acid. Metabolic activity was increased in the ipsilateral substantia nigra pars reticulata; this effect was most pronounced in the cat treated with deoxyglucose 5 min after kainic acid. Metabolism was increased in the ipsilateral deeper layers of the colliculus superior in the cat that received deoxyglucose 70 min after kainic acid. The present behavioural and metabolic data suggest that kainic acid produces an increasing pathology resulting successively in functional changes in the caudate nucleus, its output-station the substantia nigra pars reticulata and the nigral output-station the deeper layers of the colliculus superior. It is suggested that the successive appearance of the latter effects is inherent in the hierarchical order of the brain structures under study. The occurrence of orofacial dyskinetic movements during the whole observation period suggests that the former movements were not mediated via the striato-nigro-collicular pathway. Finally, apomorphine injected in the ipsilateral caudate nucleus 1 week after kainic acid was significantly less effective compared to apomorphine injected 1 week before kainic acid. The clinical implications of the present data are discussed.

The findings in this feline study indicate that the enkephalin-positive subcommissural part of the globus pallidus, which is known to contain GABA and cholinergic cells projecting to the cortex, is innervated by the anterodorsal region of the caudate nucleus, but not by the core. Like stimulation of a particular subclass of dopamine receptors in the anterodorsal region of the caudate nucleus, inhibition of the GABA receptors in the noted part of the globus pallidus resulted in orofacial dyskinesia, viz. tic-like contractions of the facial, eye and ear muscles, and tongue protrusions. This phenomenon was elicited by intrapallidal injections of the GABA antagonist picrotoxin in a dose-dependent manner and could be attenuated by the GABA agonist muscimol. Previous studies have already shown that neither stimulation of the dopamine receptors in the core of the caudate nucleus nor any manipulation with the first- and second-order output-stations of the latter brain region, viz. (a) those regions of the substantia nigra, pars reticulata which receive afferents from the caudate nucleus, and (b) those regions of the intermediate layers of the superior colliculus which receive afferents from the latter nigral region, ever resulted in orofacial dyskinesia. These findings support the hypothesis that the anatomically distinct input-output channels of the caudate nucleus are differentially involved in orofacial dyskinesia. The clinical impact of these findings is discussed in view of the L-3,4-dihydroxyphenylalanine-induced tardive dyskinesia in man. In addition, the relevance of the anatomical data is discussed in view of the co-occurrence of Parkinson's Disease and Dementia of Alzheimer-type in certain patients.