Positron emission tomographic analysis of central D1 and D2 dopamine receptor occupancy in patients treated with classical neuroleptics and clozapine. Relation to extrapyramidal side effects.

Positron emission tomography and selective radioligands were used to determine D1 and D2 dopamine receptor occupancy induced by neuroleptics in the basal ganglia of drug-treated schizophrenic patients. In 22 patients treated with conventional dosages of classical neuroleptics, the D2 occupancy was 70% to 89%. Patients with acute extrapyramidal syndromes had a higher D2 occupancy than those without side effects. This finding indicates that neuroleptic-induced extrapyramidal syndromes are related to the degree of central D2 occupancy induced in the basal ganglia. In five patients treated with clozapine, the prototype atypical antipsychotic drug, a lower D2 occupancy of 38% to 63% was found. This finding demonstrates that clozapine is also "atypical" with respect to the central D2 occupancy in patients. During treatment with clozapine, there is a low frequency of extrapyramidal syndromes, which accordingly may reflect the comparatively low D2 occupancy induced by clinical doses of clozapine. Classical neuroleptics, like haloperidol or sulpiride, did not cause any evident D1 occupancy, but the thioxanthene flupentixol induced a 36% to 44% occupancy. In four patients treated with clozapine, the D1 occupancy was 38% to 52%. The D1 occupancy induced by clozapine and flupentixol may contribute to the antipsychotic effect of these drugs.     

Clozapine-, but not haloperidol-, induced increases in deltaFosB-like immunoreactivity are completely blocked in the striatum of mice lacking D3 dopamine receptors

On the basis of anatomical and pharmacological evidence, we have proposed that D3 receptor antagonism plays a role in the mediation of clozapine-, but not haloperidol-, induced immediate-early gene expression in the striatum. To test this hypothesis directly, we compared the effects of repeated administration of vehicle (8 mL/kg/day), clozapine (20 mg/kg/day) and haloperidol (2 mg/kg/day) for 17 days on expression of deltaFosB-like immunoreactivity (deltaFosB-Ir) in the island of Calleja major, nucleus accumbens and caudate-putamen of wild-type C57Bl6 (WT) and D3 receptor knockout (D3KO) mice. In vehicle-treated mice, the number of deltaFosB-Ir neurons in the nucleus accumbens was greater in D3KO than in WT mice. This finding is consistent with results implicating D3 receptor activation in the tonic inhibition of this limbic structure. Unlike rats, clozapine significantly increased the number of deltaFosB-Ir neurons in both the nucleus accumbens and the caudate-putamen of WT mice albeit to a lesser extent in the caudate-putamen than nucleus accumbens. Similar to rats, however, deltaFosB-Ir in the island of Calleja major of WT mice was elevated by clozapine but not by haloperidol. In the nucleus accumbens and caudate-putamen, haloperidol produced similar increases in deltaFosB-Ir in WT and D3KO mice. By contrast, clozapine-induced increases in deltaFosB-Ir in the island of Calleja major, nucleus accumbens and caudate-putamen of WT mice were absent in D3KO mice. These findings, which indicate that D3 receptor blockade is essential for clozapine-induced increases in striatal deltaFosB-Ir, suggest that D3 receptor antagonism may contribute to the unique therapeutic profile of this atypical antipsychotic.     

Comparative postnatal development of dopamine D1, D2 and D4 receptors in rat forebrain

Postnatal development of dopamine D(1), D(2) and D(4) receptors in the caudate-putamen, nucleus accumbens, frontal cortex and hippocampus was assessed in rat brain between postnatal days 7 and 60. In the caudate-putamen and nucleus accumbens, density of all three receptor subtypes increased to a peak at postnatal day 28, then declined significantly in both regions (postnatal days 35-60) to adult levels. In the frontal cortex and hippocampus, these receptors rose steadily and continuously to stable, maximal adult levels by postnatal day 60. Evidently, D(1), D(2) and D(4) receptors follow a similar course of development in several cortical, limbic and extrapyramidal regions of rat forebrain, with selective elimination of excess dopamine receptors at the time of puberty in the caudate-putamen and accumbens but not other brain regions.     

Chronic treatment with clozapine or haloperidol differentially regulates dopamine and serotonin receptors in rat brain

Long-term administration of the atypical neuroleptic clozapine (CLZ) poses a much lower risk of extrapyramidal side effects (EPS) than does the use of typical neuroleptics such as haloperidol (HAL). To investigate the neural mechanisms of the differing CNS activities of these two drugs, we used quantitative autoradiography to measure changes in dopamine and serotonin receptors in rats after injection with CLZ or HAL for 21 days at clinically relevant dose ratios. Levels of D1, D2, and 5-HT2 receptors were determined in frontal cortex, caudate-putamen, and nucleus accumbens. Rats that received CLZ chronically showed CNS receptor changes markedly different from those in chronic HAL-treated animals. Whereas rats treated chronically with HAL showed enhanced striatal D2 binding (average increase of 42%), those treated with CLZ did not. In contrast, chronic CLZ, but not chronic HAL, induced enhanced striatal D1 binding (average increase of 43%). Finally, CLZ treatment decreased 5-HT2 receptor binding by an average of 37%, while HAL had no significant effect. The effects of chronic HAL or CLZ treatment on receptors were similar in all forebrain areas examined. However, since D1 and 5-HT2 receptors are more abundant than D2 sites in limbic and neocortical areas, the preferential modulation of D1 and 5-HT2 receptors by CLZ suggests a greater impact of this atypical neuroleptic on activity of the limbic system than that achieved by the typical neuroleptic, HAL. These findings suggest that the clinical profile of atypical neuroleptics such as CLZ may be attributed to their effects on a receptor profile differing in pharmacological characteristics and anatomical distribution from that affected by typical neuroleptics.     

Properties of D2 dopamine receptor autoradiography: High percentage of high-affinity agonist sites and increased nucleotide sensitivity in tissue sections

[3H]Spiroperidol (spiperone) binding in the presence of mianserin, a serotonin (5-HT2) receptor antagonist, was characterized in rat brain using quantitative autoradiography. All binding parameters were directly determined from film densities. Competition and kinetic studies revealed that [3H]spiroperidol binds to a site having characteristics of the dopamine, D2, receptor in striatum. The general binding parameters were similar to values obtained in homogenate and swabbed section studies except as related to agonist binding and guanine nucleotide sensitivity. Competition studies with dopamine revealed biphasic competition curves with a Kh of 8.23 nM and a Kl of 12.3 microM. The percentage of high-affinity sites was 90%. Guanine nucleotides (1 microM guanylyl-imidodiphosphate) completely converted the high-affinity site to a low-affinity site. Quantitative regional distribution studies revealed high binding in striatum, olfactory tubercle and nucleus accumbens, with lower binding in other dopamine innervated regions including frontal and cingulate cortex. [3H]Spiroperidol was also found to bind to a spirodecanone site with an anatomical localization distinct from the dopamine and serotonin systems and in a region (entorhinal cortex) not previously reported. This report provides a detailed pharmacologic and regional characterization of [3H]spiroperidol binding to D2 receptor in rat brain using quantitative autoradiography to determine all binding parameters. This report also demonstrates an increased percentage of sites in the high-affinity state of the D2 receptor in tissue sections and increased affinity of the guanine regulatory protein for guanine nucleotides.     

Regional selectivity of neuroleptic drugs: An argument for site specificity

Differences among neuroleptic drugs in their abilities to produce extrapyramidal side-effects have alternatively been ascribed to their inherent anticholinergic effect or their preferential action with particular brain areas. Animal behavioral studies in rats, with the intralimbic or intrastriatal injection of dopamine demonstrate that atypical neuroleptics, i.e., clozapine, thioridazine, show a greater relative preference for blocking dopamine's limbic actions. Studies using the rat model of tardive dyskinesia (neuroleptic-induced behavioral hypersensitivity), suggest that the atypical neuroleptics are again unique. Receptor ligand studies in rat brain and human brain, using 3H-spiroperidol, show that haloperidol produces a preferential blockade of striatal receptor sites, whereas clozapine and thioridazine are most active at limbic sites. Biochemical data in animals and clinical data in man are reviewed to further support the concept of site specificity.     

Multiple neurochemical action of clozapine: A quantitative autoradiographic study of DA 2, opiate and benzodiazepine receptors in the rat brain after long-term treatment

Summary The atypical neuroleptic clozapine has clinical and behavioral properties that differ not only from the typical compounds, but also from atypical ones. It interacts with the dopaminergic systems, but also produces effects on the serotoninergic, GABA-ergic, cholinergic systems. In spite of the amount of papers devoted to its study, the profile of the neurochemical action of this drug is still confuse. In this paper we investigated the DA 2-, opiate- and benzodiazepine-receptor modifications induced by the long term (21 days) treatment with clozapine 20 mg/kg/day in the rat brain. We found a decrease of DA 2 receptor density in the target areas of the mesolimbocortical system (ventral n. caudate-putamen, cerebral cortex except for the anterior cingulate at the most anterior level and the n. accumbens) and a decrease of opiate and benzodiazepine receptors in the cerebral cortex and in the olfactory tubercle. Opiate receptors increase in the patches of the striatum. We also compared these effects with those produced by long-term (21 days), low-dosage (0.5 mg/kg day) haloperidol.     

Effects of haloperidol and clozapine on Fos expression in the primate striatum

In cynomolgus monkeys, the typical neuroleptic haloperidol induced strong expression of the immediate early gene product Fos in both the nucleus accumbens shell and the dorsal striatum. In the caudate nucleus, haloperidol induced staining was more marked in the striosomes than the matrix. The atypical neuroleptic clozapine also induced Fos expression in the nucleus accumbens, but, in contrast to haloperidol, had only a small effect in the dorsal striatum. Additionally, clozapine was more potent than haloperidol at inducing Fos-like immunoreactivity in the islands of Calleja. These results are similar to those typically obtained in rodents, and suggest that the basic mechanisms underlying the regional specificity of the effects of atypical neuroleptics are likely be conserved between these two mammalian orders.     

Autoradiographic studies in animal models of hemi-parkinsonism reveal dopamine D2 but not D1 receptor supersensitivity. I. 6-OHDA lesions of ascending mesencephalic dopaminergic pathways in the rat

The selective dopaminergic antagonist ligands [3H]SCH 23390 and [3H]sulpiride were used to reveal autoradiographically dopamine D1 and D2 receptors, respectively, in brain sections from rats which had received unilateral 6-hydroxydopamine (6-OHDA) injections destroying ascending nigrostriatal neurones. The binding of both ligands to striatal sections was first shown to be saturable, reversible and of high affinity and specificity [( 3H]SCH 23390: Bmax 2.16 pmol/mg protein, Kd 1.4 nM; [3H]sulpiride; Bmax 0.67 pmol/mg protein, Kd 10.7 nM). After unilateral stereotaxic 6-OHDA injections, rats rotated contralaterally when challenged with apomorphine (0.5 mg/kg), or specific D1 or D2 agonists, SKF 38393 (1.0-5.0 mg/kg) and LY 171555 (0.05-0.5 mg/kg), respectively. Loss of forebrain dopaminergic terminals was assessed autoradiographically using [3H]mazindol to label dopamine uptake sites. A loss of approximately 90-95% of uptake sites was reproducibly accompanied by an enhanced density of binding ipsilaterally for the D2 ligand, [3H]sulpiride, in all areas of the striatum, but most markedly in the lateral areas. An increase in the D2 binding site density was also seen in the ipsilateral nucleus accumbens and the olfactory tubercle. In contrast, in the same animals, the striatal D1 receptors were far less affected by dopaminergic denervation, with no consistent changes seen in the binding of [3H]SCH 23390. These results suggest that dopamine D2 receptors are more susceptible than D1 receptors to changes after dopaminergic denervation, which is expressed as an increase in the density of binding sites revealed here with [3H]sulpiride.     

Autoradiographic localization and quantification of dopamine D2 receptors in normal human brain with [H]N-n-propylnorapomorphine

The precise distribution of dopamine receptors has been studied autoradiographically in the normal human brain using [³H]N-n-propylnorapomorphine ([³H]NPA) as a ligand. Preliminary experiments aimed at optimizing the binding assay conditions revealed that preincubation washing of caudate nucleus sections was a prerequisite to obtain a good ratio of specific to non-specific binding. The binding of [³H]NPA to caudate-putamen sections was saturable, stereospecific, reversible, of high affinity (K_d = 0.27–0.35 nM) and occurred at a single population of sites. Competition experiments with various drugs indicated that in the caudate-putamen the specific [³H]NPA binding sites possess the pharmacological features of the dopamine D₂ receptor. The highest levels of [³H]NPA binding sites were found in the caudate nucleus, putamen, globus pallidus and nucleus accumbens. There were also intermediate to low concentrations of the ³H-ligand in the hippocampus, the insular and cingular cortices and in the occipito-temporal gyrus, while almost undetectable levels of binding were found in the anteior frontal cortex. Thorough examination of the subregional distribution of [³H]NPA binding sites in the caudate-putamen-pallidum complex revealed heterogenous patterns of radioactivity. In these brain regions, the distribution of autoradiographic grains was punctate and islands of high and low densities were observed. Moreover, in the caudate nucleus, there was a subtle high lateral to low medial gradient in the topography of the [³H]NPA binding sites and a more pronounced gradient along the rostrocaudal axis; the highest levels of binding being located at the midbody of the nucleus. No gradients of [³H]NPA binding were observed in the putamen. The present data indicate that [³H]NPA is a suitable ligand for accurate autoradiographic labeling of dopamine D₂ receptors in human postmortem brain tissue and that dopamine receptors are heterogeneously distributed and topographically organized in patches and gradients in the basal ganglia regions.     

D1 and D2 receptor modulation in rat striatum and nucleus accumbens after subchronic and chronic haloperidol treatment

The antipsychotic effects of neuroleptic drugs are believed to be achieved by chronic blockade of dopaminergic transmission in the limbic system. Nevertheless, the effects of chronic (3-12 months) haloperidol administration on the dopaminergic transmission in the nucleus accumbens of rodents remains poorly understood. Studies of spontaneous locomotor activity (SLA), a behavioral measure related to limbic dopamine transmission, and of dopamine D2 receptor density in the nucleus accumbens after chronic oral haloperidol treatment have yielded conflicting results. We evaluated these indices after 8 months of parenteral administration of haloperidol decanoate. We report here that, after 8 months of parenteral treatment, SLA stays significantly decreased and D2 receptors in the nucleus accumbens exhibit the same up-regulation as in the striatum (about 50%). These results fail to support the notion of a different pattern of D2 receptor adaptation to neuroleptic treatment between the nucleus accumbens and the striatum. In contrast, dopamine D1 receptors were found to be unaffected in the nucleus accumbens but decreased in the striatum by 22% after 8 months of treatment. This observation could be relevant to the pathogenesis of tardive dyskinesia.     

Contrasting Effects of Chronic Clozapine, SeroquelTM (ICI 204,636) and Haloperidol Administration on ΔFosB-like Immunoreactivity in the Rodent Forebrain

We have recently demonstrated that specific neuroanatomical patterns of Fos-like immunoreactivity are predictive of atypical antipsychotic activity. However, the fact that neuroleptics must be administered chronically in order to generate both extrapyramidal side effects and an optimal therapeutic response calls into question the relevance of acute changes in Fos-like immunoreactivity for these slowly developing events. Fos-like immunoreactivity cannot be used to identify neurons activated by chronic neuroleptic administration because the increase in Fos-like immunoreactivity produced by an acute antipsychotic injection is dramatically reduced following repeated neuroleptic administration. In contrast, expression of the immediate-early gene product ΔFosB is persistently elevated in the striatum by chronic haloperidol administration. This suggests that ΔFosB-like immunoreactivity may be used to identify neurons activated by chronic antipsychotic administration. Since typical and atypical neuroleptics elevate Fos-like immunoreactivity in different regions of the forebrain acutely, the purpose of the present study was to determine whether typical (haloperidol) and atypical (clozapine, ICI 204,636) antipsychotics produce distinct patterns of elevated ΔFosB-like immunoreactivity in the forebrain after chronic administration. Administration of haloperidol (2 mg/kg/day) to rats for 19 days induced a homogeneous elevation of neurons which displayed ΔFosB-like immunoreactivity in the ventral, medial and dorsolateral aspects of the striatum. Chronic haloperidol administration did not enhance ΔFosB-like immunoreactivity in the prefrontal cortex and lateral septal nucleus. Repeated administration of clozapine (20 mg/kg/day) and ICI 204,636 (20 mg/kg/day) for 19 days elevated ΔFosB-like immunoreactivity not only in the ventral striatum but also in the prefrontal cortex and lateral septal nucleus. However, these compounds had weak effects on ΔFosB-like immunoreactivity in the dorsolateral striatum. These results suggest that a preferential action on limbic structures such as the prefrontal cortex, ventral striatum and lateral septal nucleus may account for the ability of chronic clozapine and ICI 204,636 administration to reduce the symptoms of schizophrenia without generating extrapyramidal side effects.     

Differential actions of classical and atypical neuroleptics on mouse nigrostriatal neurons

1. 1. The classical neuroleptics haloperidol, perphenazine and chlorpromazine increase both dopamine metabolism and release in the mouse striatum.

2. 2. The atypical agents clozapine and thioridazine increase dopamine metabolism with no increase in release.

3. 3. At high doses, sulpiride increases both dopamine metabolism and release.

4. 4. These data suggest that atypical neuroleptics act to inhibit dopamine release and indicate that sulpiride may not be an atypical agent.

Autoradiography of dopamine receptors and dopamine uptake sites in the spontaneously hypertensive rat

We examined the status of dopamine (DA) D1 and D2 receptors by using [3H]SCH 23390 and [3H]spiperone binding, respectively, and DA uptake sites by using [3H]mazindol binding in spontaneously hypertensive rats (SHR) and Sprague-Dawley (SD) rats. SHR showed significantly higher [3H]SCH 23390 and [3H]spiperone binding in the caudate-putamen (CPu), the nucleus accumbens (NAc) and the olfactory tubercle (OT) in comparison to the SD rats. There were no significant differences in [3H]mazindol-labeled DA uptake sites between the two strains. Unilateral 6-hydroxydopamine (6-OHDA) injection into the striatum resulted in more than 90% depletion of DA uptake sites in the CPu in both strains. 6-OHDA-induced DA depletion was associated with significant increases in striatal [3H]spiperone binding which were of similar magnitude in the SD rats (+64.1%) and SHR (+51.3%). There were only small decreases (-5.4%) in D1 receptor binding in the dorsolateral aspect of the CPu in the SHR, whereas there were no changes in striatal D1 receptors in the SD rats. These results indicate that, although the SHR have higher concentrations of both D1 and D2 receptors in the basal ganglia, these receptors are regulated in a fashion similar to DA receptors in SD rats after 6-OHDA-induced striatal DA depletion.     

Distinct and interactive effects of d-amphetamine and haloperidol on levels of neurotensin and its mRNA in subterritories in the dorsal and ventral striatum of the rat

Striatal tissue concentrations of neurotensin, expression of neurotensin/neuromedin N (NT/N) mRNA, and numbers of neurotensin-immunoreactive neurons are increased by d-amphetamine (amph), which stimulates dopamine release in the striatum, and haloperidol (hal), a dopamine receptor antagonist with high affinity for D_2-like receptors. The possibility that the effects of these drugs involve distinct subpopulations of striatal neurons was addressed in this study, in which the relative numbers and distributions of striatal neuron profiles containing neurotensin immunoreactivity and/or NT/N mRNA were compared following administrations of hal, amph, hal and amph co-administered, and vehicle. Fourteen striatal subterritories in caudate-putamen, nucleus accumbens, and olfactory tubercle were evaluated. Amph produced increases in the expression of neurotensin preferentially in the ventromedial and caudodorsal subterritories of the caudate-putamen, the rostrobasal cell cluster and lateral shell of the nucleus accumbens, and the olfactory tubercle. Haloperidol produced increased neurotensin expression in much of dorsal and ventral striatum, most prominently in the rostral, dorsomedial and ventrolateral quadrants of the caudate-putamen, and in the rostrobasal cell cluster, rostral pole, medial and lateral shell of the nucleus accumbens and the olfactory tubercle. The numbers of neurons responding to amph and hal in all subterritories following co-administration of the two drugs were significantly less than the summed numbers responding individually to amph and hal. Furthermore, in the subterritories where immunohistochemically detectable responses elicited by amph exceeded those produced by hal, co-administration of the two drugs resulted in responses comparable to those elicited by hal given alone. It is suggested that some of the reported anti-dopaminergic behavioral effects of basal ganglia neurotensin may be attenuated in conditions of reduced dopamine neurotransmission. J. Comp Neurol. 400:487–503, 1998. © 1998 Wiley-Liss, Inc.     

Dopamine D2 receptors exert tonic regulation over discrete neurotensin systems of the rat brain

Blockade of dopamine D₂ receptors with either the selective antagonist, sulpiride, or the non-selective antagonist, haloperidol, induces 2- to 3-fold increases in the content of neurotensin-like immunoreactivity in the striatum and the nucleus accumbens of the rat brain. Quantitatively similar increases were also observed (a) in the striatum following selective degeneration of more than 85% of the nigrostriatal dopamine pathway with 6-hydroxydopamine and (b) in both the striatum and the nucleus accumbens after non-selective depletion of brain dopamine using reserpine plus α-methyl-p-tyrosine. Interestingly, treatment of animals with sulpiride or haloperidol, following the depletion of dopamine by either 6-hydroxydopamine or reserpine plus α-methyl-p-tyrosine, did not add to the elevation in neurotensin content of either structure caused by the dopamine depletion alone. These data suggest that an intact dopamine system is required for the neuroleptics to exert effects on individual neurotensin systems. In addition, the same mechanism appears to underlie the responses of the neurotensin pathways to treatments with the neuroleptics or dopamine-depleting drugs. A likely explanation for the effects of neuroleptics and dopamine-depleting drugs is that they eliminate tonic activity on D₂ receptors by basally released dopamine in the striatum and the nucleus accumbens. Supportive evidence for this hypothesis is that concurrent administration of the D₂ receptor agonist, LY 171555, with reserpine, completely blocked the effects of reserpine-induced dopamine depletion on neurotensin systems of the striatum and the nucleus accumbens.     

Effects of D2 dopamine receptor antagonists on fos protein expression in the striatal complex and entorhinal cortex of the nonhuman primate

Recent studies have reported that acute administration of dopamine D₂ receptor antagonists increases expression of the immediate early gene c-fos in the rat striatal complex. There have been no corresponding studies of the effects of D₂ antagonists in primate species. Since all clinically effective antipsychotic drugs share D₂ receptor antagonism, it is important to define the extent to which these drugs may alter expression of c-fos or its protein product, Fos, in primates. We therefore examined the effects of administration of two D₂ receptor antagonists, haloperidol and metoclopramide, on Fos expression in the striatum and temporal cortices of the vervet monkey. Metoclopramide does not appear to possess significant antipsychotic efficacy but potently produces extrapyramidal side effects, while haloperidol is an effective antipsychotic drug that produces extrapyramidal side effects. Both drugs increased the number of Fos-like immunoreactive (Fos-li) neurons in the caudate nucleus and putamen; the numbers of Fos-li neurons in these regions were increased in both the patch and matrix compartments. Haloperidol but not metoclopramide increased the number of Fos-li neurons in the nucleus accumbens shell. Similarly, haloperidol but not metoclopramide increased the number of Fos-li neurons in the entorhinal cortex. Neither drug altered Fos expression in the inferior temporal cortex. These data suggest that the dorsolateral caudate nucleus and putamen may be sites at which D₂ receptor antagonists elicit extrapyramidal side effects, and the nucleus accumbens shell and entorhinal cortex may be loci at which the therapeutic actions of antipsychotic drugs are manifested. © 1996 Wiley-Liss, Inc.     

FosB in rat striatum: normal regional distribution and enhanced expression after 6-month haloperidol administration

Subcortical motor nuclei show differential expression of FosB immediate early gene products and specifically deltaFosB after short (8, 19, or 21 days) chronic exposure to typical and atypical neuroleptics represented by haloperidol and clozapine, respectively. We quantitatively examined whether there are light microscopic regional variations in area density of FosB or the truncated deltaFosB in several motor-related nuclei of adult rats receiving vehicle or long chronic (6 months) administration of either depot haloperidol or clozapine in their drinking water. In control animals the dorsomedial and ventromedial caudate-putamen nucleus (CPN) had a significantly higher density of FosB-immunoreactive cells than the dorsolateral and ventrolateral regions. The nucleus accumbens (NAc) core also serving motor functions had a higher basal expression than the limbic shell region in control animals. The mediolateral gradient in area density of FosB-labeled cells was maintained in animals receiving either haloperidol or clozapine. In animals receiving haloperidol, but not clozapine, however, there was a regionally selective increase in the area density of only FosB-immunoreactive neurons in the dorsolateral and ventrolateral CPN and in both the core and shell of the NAc. Only the animals receiving chronic haloperidol showed vacuous chewing movements, the animal equivalent of tardive dyskinesia in humans. Our results suggest that, whereas the medial striatal neurons are activated under basal conditions, long chronic haloperidol induced FosB expression more exclusively in the lateral CPN and NAc core, implicating these regions specifically in the motor side effects of this drug.