EDITORIAL
A Late Appearance by the Dopamine D-3 Receptor Peter Jenner, PhD* Neurodegenerative Disease Research Group, Institute of Pharmaceutical Sciences, School of Biomedical Sciences, King’s College, London, United Kingdom
The D-3 dopamine receptor was first cloned in 1990 and was shown to be present largely in limbic regions of the brain, with much lower levels expressed in striatal areas.1 Many neuroleptic drugs, as well as dopamine agonists, were shown to interact with D-3 receptors and in some cases with a higher affinity than for D-2 receptors (including haloperidol and clozapine, but see McCormick et al.2). In subsequent years, the D-3 receptor was targeted as a site of action for potential novel antipsychotic drugs, but this aspiration has yet to be achieved.3 More recently, alterations in D-3 receptor density were examined in relation to Parkinson’s disease (PD) in tissues from 6hydroxydopamine (6-OHDA) lesioned rat and 1methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)treated primates, and in post-mortem tissues from individuals dying with PD. Some studies found a proliferation of D-3 receptors in the striatum after exposure to levodopa and specifically in animals that developed abnormal involuntary movements (AIMs) or dyskinesia,4,5 although no consensus was reached.6-9 Subsequently D-3 antagonists or partial agonists were shown to suppress levodopa-induced dyskinesia in MPTP-treated primates10,11 and to prevent dyskinesia induction.12 These studies served to establish a link between the D-3 receptor and involuntary movements, at least in PD. As with dyskinesia in PD, the genesis of tardive dyskinesia (TD) occurring as a result of exposure to antipsychotic drugs has proved difficult to unravel. The late occurrence of dyskinetic movements, classically affecting the oro-buccal-facial-lingual areas, was initially associated with typical neuroleptic agents, but it is now known to occur with second-generation atypi-
------------------------------------------------------------
*Correspondence to: Professor Peter Jenner, NDRG, Hodgkin Building, King’s College, London SE1 1UL, United Kingdom, E-mail: [email protected] Funding agencies: This editorial was not supported by any research funding.
Relevant conflicts of interest/financial disclosures: Peter Jenner is Emeritus Professor of Pharmacology at King’s College London. Full financial disclosures and author roles may be found in the online version of this article. Received: 24 May 2014; Accepted: 2 June 2014 Published online 7 July 2014 in Wiley Online Library (wileyonlinelibrary.com) DOI: 10.1002/mds.25958
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cal antipsychotics, although to a lesser degree.13 The exception to this rule is clozapine, whose actions have never been explained or mimicked. The classical explanation for TD has been that D-2 receptor sensitization takes place, but this has never been totally satisfactory.14 Some similarities have been seen in markers of striatal output pathway function that are changed in response to chronic administration of antiparkinsonian drugs in 6-OHDA lesioned rats and normal rats treated chronically with classical antipsychotic drugs. This suggests that despite opposing actions on postsynaptic striatal dopamine receptors, dopamine agonist and antagonist compounds might induce common changes linked to dyskinesia induction, and that brings us back to the role that D-3 receptors might play in the induction of TD. One problem has been the veracity of the studies needed to explore the pathophysiology of TD in terms of time required for drug treatment to lead to induction and expression of late onset dyskinesia. However, the chronic administration of neuroleptic drugs to both Old and New World monkeys has long been known to lead to the late onset of dyskinetic movements.15-17 Cebus apella (capuchin monkeys) are considered more susceptible to the development of TD, and one reason may relate to the Ser9Gly polymorphism that they carry in the D-3 receptor gene, which has been suggested as a susceptibility factor for the development of TD in some populations.18,19 This may be highly relevant to the studies now reported by Mahmoudi and colleagues, in which they have compared the effects of haloperidol and clozapine administration for up to 36 months on the expression of D-1, D-2, and D-3 receptors and markers of striatal output pathway activity in Cebus apella.20 In their study, the administration of haloperidol for 36 months resulted in mild dyskinetic movements, which they described in a previous publication.21 Dyskinesia appeared with a latency of some 19 months in some animals but not in others, so providing one essential control group for the effect of drug treatment alone. In clozapine-treated animals, no dyskinetic movements were seen, although, as the authors point out, the 6-month period of treatment may not have been sufficiently long. A
L A T E
A P P E A R A N C E
neuroadaptive response to haloperidol treatment and to dyskinesia appearance was suggested by the authors based on changes in the expression of the transcription factor Nurr77.21 The present paper shows no change in D-2 receptor density, a fall in D-1 receptor expression, but a marked increase in the expression of D-3 receptors in the striatum in those haloperidol-treated animals showing TD. Although D-3 receptor density changes were seen in all haloperidol-treated animals, a linear relationship was found between the extent of D-3 receptor expression and dyskinesia intensity. The D-3 receptor changes occurred on strio-nigral neurons, which have previously been implicated in dyskinesia induction and expression. Interestingly, enkephalin messenger RNA, which is associated with the the striopallidal pathway, was increased in all animals but less so in those showing TD. This seems to echo a shift in the balance of the direct and indirect output pathways already implicated in dyskinesia occurring in PD.22 All of the data lead the authors to dismiss the D-2 receptor concept of TD induction and to suggest that D-3 antagonists might form an effective means of treating TD, as suggested by previous pharmacological manipulation in primates.23 Too few studies seek to understand the basis of TD, and to do so in primates over a period of years requires determination. Picking holes in such studies is easy, because it is impossible to cover all the necessary bases in one such investigation. However, before we accept the D-3 concept of TD, some issues regarding relevance do need to be addressed. The dyskinetic movements observed certainly appeared late and then were constant in appearance relative to drug treatment, but whether, like TD, they persisted for significant periods of time after stopping drug administration is not clear. With respect to the biochemical changes observed, when these appeared relative to the onset of TD is not known. Were they present much earlier and, indeed, would they persist once drug treatment was stopped and mirror dyskinesia? Notably the animals were killed 3 h after a final oral drug treatment-a longer period of withdrawal might have been more prudent. Then of course there is the chicken and egg argument. Were the receptor changes a cause or a consequence of the dyskinetic movements? In this respect, one must bear in mind that the animals used had shown parkinsonian features and bouts of acute dystonia in addition to late onset dyskinesia. Finally, we must not look at these changes in dopamine receptor expression in isolation. What happened to other neuronal systems key to dyskinesia expression—glutamate receptors, adenosine receptors, 5-HT receptors, and so forth? No doubt studies on these will follow, using the same tissues. It does seem unlikely that an isolated alteration in
B Y
D O P A M I N E
D - 3
R E C E P T O R
D-3 receptor expression is the whole story for the appearance of TD. In conclusion, the study by Mahmoudi and colleagues20 has opened up a new era of investigation into the underlying biochemical causes of TD that has not had the intensity of research in recent times that it deserves relative to its clinical significance. Perhaps in the glow of publicity about the lower risks of extrapyramidal side effects of new-generation atypical antipsychotics13 it fell into the shadows. TD is now emerging as a result of this study, and if correct, D-3 antagonists may provide a pharmacological means of controlling a longstanding clinical problem.
References 1.
Sokoloff P, Giros B, Martres MP, Bouthenet ML, Schwartz JC. Molecular cloning and characterization of a novel dopamine receptor (D3) as a target for neuroleptics. Nature. 1990;347:146151.
2.
McCormick PN, Wilson VS, Wilson AA, Remington GJ. Acutely administered antipsychotic drugs are highly selective for dopamine D2 over D3 receptors. Pharmacol Res 2013;70: 66-71.
3.
Sokoloff P, Diaz J, Le Foll B, Guillin O, Leriche L, Bezard E, et al. The dopamine D3 receptor: a therapeutic target for the treatment of neuropsychiatric disorders. CNS Neurol Disord Drug Targets 2006;5:25-43.
4.
Guigoni C, Aubert I, Li Q, et al. Pathogenesis of levodopa-induced dyskinesia: focus on D1 and D3 dopamine receptors. Parkinsonism Relat Disord. 2005;11(Suppl 1):S25-S29.
5.
Bordet R, Ridray S, Schwartz JC, Sokoloff P. Involvement of the direct striatonigral pathway in levodopa-induced sensitization in 6-hydroxydopamine-lesioned rats. Eur J Neurosci 2000;12:2117123.
6.
Hurley MJ, Jenner P. What has been learnt from study of dopamine receptors in Parkinson’s disease? Pharmacol Ther 2006;111: 715-728.
7.
Hurley MJ, Jolkkonen J, Stubbs CM, Jenner P, Marsden CD. Dopamine D3 receptors in the basal ganglia of the common marmoset and following MPTP and L-DOPA treatment. Brain Res 1996;709:259-264.
8.
Quik M, Police S, He L, Di Monte DA, Langston JW. Expression of D(3) receptor messenger RNA and binding sites in monkey striatum and substantia nigra after nigrostriatal degeneration: effect of levodopa treatment. Neuroscience 2000; 98:263-273.
9.
Piggott MA, Marshall EF, Thomas N, et al. Striatal dopaminergic markers in dementia with Lewy bodies, Alzheimer’s and Parkinson’s diseases: rostrocaudal distribution. Brain 1999;122:14491468.
10.
Bezard E, Ferry S, Mach U, et al. Attenuation of levodopa-induced dyskinesia by normalizing dopamine D3 receptor function. Nat Med 2003;9:762-767.
11.
Hsu A, Togasaki DM, Bezard E, et al. Effect of the D3 dopamine receptor partial agonist BP897 [N-[4-(4-(2-methoxyphenyl)piperazinyl)butyl]-2-naphthamide] on L-3,4-dihydroxyphenylalanineinduced dyskinesias and parkinsonism in squirrel monkeys. J Pharmacol Exp Ther 2004;311:770-777.
12.
Visanji NP, Fox SH, Johnston T, Reyes G, Millan MJ, Brotchie JM. Dopamine D3 receptor stimulation underlies the development of L-DOPA-induced dyskinesia in animal models of Parkinson’s disease. Neurobiol Dis 2009;35:184-192.
13.
Woods SW, Morgenstern H, Saksa JR, et al. Incidence of tardive dyskinesia with atypical versus conventional antipsychotic medications: a prospective cohort study. J Clin Psychiatry 2010;71:463474.
14.
Marsden CD, Jenner P. The pathophysiology of extrapyramidal side-effects of neuroleptic drugs. Psychol Med 1980;10:55-72.
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J E N N E R
15.
Gunne LM, Barany S. Haloperidol-induced tardive dyskinesia in monkeys. Psychopharmacology (Berl) 1976;50:237-240.
16.
Klintenberg R, Gunne L, Andren PE. Tardive dyskinesia model in the common marmoset. Mov Disord 2002;17:360-365.
17.
Peacock L, Jensen G, Nicholson K, Gerlach J. Extrapyramidal side effects during chronic combined dopamine D1 and D2 antagonist treatment in Cebus apella monkeys. Eur Arch Psychiatry Clin Neurosci 1999;249:221-226.
with tardive dyskinesia in humans. Pharmacogenomics J 2003;3: 97-100. 20.
Mahmoudi S, Levesque D, Blanchet PJ. Upregulation of dopamine D3, not D2, receptors correlates with tardive dyskinesia in a primate model. Mov Disord 2014;29:1124-1132.
21.
Mahmoudi S, Blanchet PJ, Levesque D. Haloperidol-induced striatal Nur77 expression in a non-human primate model of tardive dyskinesia. Eur J Neurosci 2013;38:2192-2198.
18.
Bakker PR, van Harten PN, van Os J. Antipsychotic-induced tardive dyskinesia and the Ser9Gly polymorphism in the DRD3 gene: a meta analysis. Schizophr Res 2006;83:185-192.
22.
Guridi J, Gonzalez-Redondo R, Obeso JA. Clinical features, pathophysiology, and treatment of levodopa-induced dyskinesias in Parkinson’s disease. Parkinsons Dis 2012;2012:943159.
19.
Werge T, Elbaek Z, Andersen MB, Lundbaek JA, Rasmussen HB. Cebus apella, a nonhuman primate highly susceptible to neuroleptic side effects, carries the GLY9 dopamine receptor D3 associated
23.
Malik P, Andersen MB, Peacock L. The effects of dopamine D3 agonists and antagonists in a nonhuman primate model of tardive dyskinesia. Pharmacol Biochem Behav 2004;78:805-810.
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Movement Disorders, Vol. 29, No. 9, 2014
A Late Appearance by the Dopamine D-3 Receptor Peter Jenner, PhD* Neurodegenerative Disease Research Group, Institute of Pharmaceutical Sciences, School of Biomedical Sciences, King’s College, London, United Kingdom
The D-3 dopamine receptor was first cloned in 1990 and was shown to be present largely in limbic regions of the brain, with much lower levels expressed in striatal areas.1 Many neuroleptic drugs, as well as dopamine agonists, were shown to interact with D-3 receptors and in some cases with a higher affinity than for D-2 receptors (including haloperidol and clozapine, but see McCormick et al.2). In subsequent years, the D-3 receptor was targeted as a site of action for potential novel antipsychotic drugs, but this aspiration has yet to be achieved.3 More recently, alterations in D-3 receptor density were examined in relation to Parkinson’s disease (PD) in tissues from 6hydroxydopamine (6-OHDA) lesioned rat and 1methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)treated primates, and in post-mortem tissues from individuals dying with PD. Some studies found a proliferation of D-3 receptors in the striatum after exposure to levodopa and specifically in animals that developed abnormal involuntary movements (AIMs) or dyskinesia,4,5 although no consensus was reached.6-9 Subsequently D-3 antagonists or partial agonists were shown to suppress levodopa-induced dyskinesia in MPTP-treated primates10,11 and to prevent dyskinesia induction.12 These studies served to establish a link between the D-3 receptor and involuntary movements, at least in PD. As with dyskinesia in PD, the genesis of tardive dyskinesia (TD) occurring as a result of exposure to antipsychotic drugs has proved difficult to unravel. The late occurrence of dyskinetic movements, classically affecting the oro-buccal-facial-lingual areas, was initially associated with typical neuroleptic agents, but it is now known to occur with second-generation atypi-
------------------------------------------------------------
*Correspondence to: Professor Peter Jenner, NDRG, Hodgkin Building, King’s College, London SE1 1UL, United Kingdom, E-mail: [email protected] Funding agencies: This editorial was not supported by any research funding.
Relevant conflicts of interest/financial disclosures: Peter Jenner is Emeritus Professor of Pharmacology at King’s College London. Full financial disclosures and author roles may be found in the online version of this article. Received: 24 May 2014; Accepted: 2 June 2014 Published online 7 July 2014 in Wiley Online Library (wileyonlinelibrary.com) DOI: 10.1002/mds.25958
1094
Movement Disorders, Vol. 29, No. 9, 2014
cal antipsychotics, although to a lesser degree.13 The exception to this rule is clozapine, whose actions have never been explained or mimicked. The classical explanation for TD has been that D-2 receptor sensitization takes place, but this has never been totally satisfactory.14 Some similarities have been seen in markers of striatal output pathway function that are changed in response to chronic administration of antiparkinsonian drugs in 6-OHDA lesioned rats and normal rats treated chronically with classical antipsychotic drugs. This suggests that despite opposing actions on postsynaptic striatal dopamine receptors, dopamine agonist and antagonist compounds might induce common changes linked to dyskinesia induction, and that brings us back to the role that D-3 receptors might play in the induction of TD. One problem has been the veracity of the studies needed to explore the pathophysiology of TD in terms of time required for drug treatment to lead to induction and expression of late onset dyskinesia. However, the chronic administration of neuroleptic drugs to both Old and New World monkeys has long been known to lead to the late onset of dyskinetic movements.15-17 Cebus apella (capuchin monkeys) are considered more susceptible to the development of TD, and one reason may relate to the Ser9Gly polymorphism that they carry in the D-3 receptor gene, which has been suggested as a susceptibility factor for the development of TD in some populations.18,19 This may be highly relevant to the studies now reported by Mahmoudi and colleagues, in which they have compared the effects of haloperidol and clozapine administration for up to 36 months on the expression of D-1, D-2, and D-3 receptors and markers of striatal output pathway activity in Cebus apella.20 In their study, the administration of haloperidol for 36 months resulted in mild dyskinetic movements, which they described in a previous publication.21 Dyskinesia appeared with a latency of some 19 months in some animals but not in others, so providing one essential control group for the effect of drug treatment alone. In clozapine-treated animals, no dyskinetic movements were seen, although, as the authors point out, the 6-month period of treatment may not have been sufficiently long. A
L A T E
A P P E A R A N C E
neuroadaptive response to haloperidol treatment and to dyskinesia appearance was suggested by the authors based on changes in the expression of the transcription factor Nurr77.21 The present paper shows no change in D-2 receptor density, a fall in D-1 receptor expression, but a marked increase in the expression of D-3 receptors in the striatum in those haloperidol-treated animals showing TD. Although D-3 receptor density changes were seen in all haloperidol-treated animals, a linear relationship was found between the extent of D-3 receptor expression and dyskinesia intensity. The D-3 receptor changes occurred on strio-nigral neurons, which have previously been implicated in dyskinesia induction and expression. Interestingly, enkephalin messenger RNA, which is associated with the the striopallidal pathway, was increased in all animals but less so in those showing TD. This seems to echo a shift in the balance of the direct and indirect output pathways already implicated in dyskinesia occurring in PD.22 All of the data lead the authors to dismiss the D-2 receptor concept of TD induction and to suggest that D-3 antagonists might form an effective means of treating TD, as suggested by previous pharmacological manipulation in primates.23 Too few studies seek to understand the basis of TD, and to do so in primates over a period of years requires determination. Picking holes in such studies is easy, because it is impossible to cover all the necessary bases in one such investigation. However, before we accept the D-3 concept of TD, some issues regarding relevance do need to be addressed. The dyskinetic movements observed certainly appeared late and then were constant in appearance relative to drug treatment, but whether, like TD, they persisted for significant periods of time after stopping drug administration is not clear. With respect to the biochemical changes observed, when these appeared relative to the onset of TD is not known. Were they present much earlier and, indeed, would they persist once drug treatment was stopped and mirror dyskinesia? Notably the animals were killed 3 h after a final oral drug treatment-a longer period of withdrawal might have been more prudent. Then of course there is the chicken and egg argument. Were the receptor changes a cause or a consequence of the dyskinetic movements? In this respect, one must bear in mind that the animals used had shown parkinsonian features and bouts of acute dystonia in addition to late onset dyskinesia. Finally, we must not look at these changes in dopamine receptor expression in isolation. What happened to other neuronal systems key to dyskinesia expression—glutamate receptors, adenosine receptors, 5-HT receptors, and so forth? No doubt studies on these will follow, using the same tissues. It does seem unlikely that an isolated alteration in
B Y
D O P A M I N E
D - 3
R E C E P T O R
D-3 receptor expression is the whole story for the appearance of TD. In conclusion, the study by Mahmoudi and colleagues20 has opened up a new era of investigation into the underlying biochemical causes of TD that has not had the intensity of research in recent times that it deserves relative to its clinical significance. Perhaps in the glow of publicity about the lower risks of extrapyramidal side effects of new-generation atypical antipsychotics13 it fell into the shadows. TD is now emerging as a result of this study, and if correct, D-3 antagonists may provide a pharmacological means of controlling a longstanding clinical problem.
References 1.
Sokoloff P, Giros B, Martres MP, Bouthenet ML, Schwartz JC. Molecular cloning and characterization of a novel dopamine receptor (D3) as a target for neuroleptics. Nature. 1990;347:146151.
2.
McCormick PN, Wilson VS, Wilson AA, Remington GJ. Acutely administered antipsychotic drugs are highly selective for dopamine D2 over D3 receptors. Pharmacol Res 2013;70: 66-71.
3.
Sokoloff P, Diaz J, Le Foll B, Guillin O, Leriche L, Bezard E, et al. The dopamine D3 receptor: a therapeutic target for the treatment of neuropsychiatric disorders. CNS Neurol Disord Drug Targets 2006;5:25-43.
4.
Guigoni C, Aubert I, Li Q, et al. Pathogenesis of levodopa-induced dyskinesia: focus on D1 and D3 dopamine receptors. Parkinsonism Relat Disord. 2005;11(Suppl 1):S25-S29.
5.
Bordet R, Ridray S, Schwartz JC, Sokoloff P. Involvement of the direct striatonigral pathway in levodopa-induced sensitization in 6-hydroxydopamine-lesioned rats. Eur J Neurosci 2000;12:2117123.
6.
Hurley MJ, Jenner P. What has been learnt from study of dopamine receptors in Parkinson’s disease? Pharmacol Ther 2006;111: 715-728.
7.
Hurley MJ, Jolkkonen J, Stubbs CM, Jenner P, Marsden CD. Dopamine D3 receptors in the basal ganglia of the common marmoset and following MPTP and L-DOPA treatment. Brain Res 1996;709:259-264.
8.
Quik M, Police S, He L, Di Monte DA, Langston JW. Expression of D(3) receptor messenger RNA and binding sites in monkey striatum and substantia nigra after nigrostriatal degeneration: effect of levodopa treatment. Neuroscience 2000; 98:263-273.
9.
Piggott MA, Marshall EF, Thomas N, et al. Striatal dopaminergic markers in dementia with Lewy bodies, Alzheimer’s and Parkinson’s diseases: rostrocaudal distribution. Brain 1999;122:14491468.
10.
Bezard E, Ferry S, Mach U, et al. Attenuation of levodopa-induced dyskinesia by normalizing dopamine D3 receptor function. Nat Med 2003;9:762-767.
11.
Hsu A, Togasaki DM, Bezard E, et al. Effect of the D3 dopamine receptor partial agonist BP897 [N-[4-(4-(2-methoxyphenyl)piperazinyl)butyl]-2-naphthamide] on L-3,4-dihydroxyphenylalanineinduced dyskinesias and parkinsonism in squirrel monkeys. J Pharmacol Exp Ther 2004;311:770-777.
12.
Visanji NP, Fox SH, Johnston T, Reyes G, Millan MJ, Brotchie JM. Dopamine D3 receptor stimulation underlies the development of L-DOPA-induced dyskinesia in animal models of Parkinson’s disease. Neurobiol Dis 2009;35:184-192.
13.
Woods SW, Morgenstern H, Saksa JR, et al. Incidence of tardive dyskinesia with atypical versus conventional antipsychotic medications: a prospective cohort study. J Clin Psychiatry 2010;71:463474.
14.
Marsden CD, Jenner P. The pathophysiology of extrapyramidal side-effects of neuroleptic drugs. Psychol Med 1980;10:55-72.
Movement Disorders, Vol. 29, No. 9, 2014
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J E N N E R
15.
Gunne LM, Barany S. Haloperidol-induced tardive dyskinesia in monkeys. Psychopharmacology (Berl) 1976;50:237-240.
16.
Klintenberg R, Gunne L, Andren PE. Tardive dyskinesia model in the common marmoset. Mov Disord 2002;17:360-365.
17.
Peacock L, Jensen G, Nicholson K, Gerlach J. Extrapyramidal side effects during chronic combined dopamine D1 and D2 antagonist treatment in Cebus apella monkeys. Eur Arch Psychiatry Clin Neurosci 1999;249:221-226.
with tardive dyskinesia in humans. Pharmacogenomics J 2003;3: 97-100. 20.
Mahmoudi S, Levesque D, Blanchet PJ. Upregulation of dopamine D3, not D2, receptors correlates with tardive dyskinesia in a primate model. Mov Disord 2014;29:1124-1132.
21.
Mahmoudi S, Blanchet PJ, Levesque D. Haloperidol-induced striatal Nur77 expression in a non-human primate model of tardive dyskinesia. Eur J Neurosci 2013;38:2192-2198.
18.
Bakker PR, van Harten PN, van Os J. Antipsychotic-induced tardive dyskinesia and the Ser9Gly polymorphism in the DRD3 gene: a meta analysis. Schizophr Res 2006;83:185-192.
22.
Guridi J, Gonzalez-Redondo R, Obeso JA. Clinical features, pathophysiology, and treatment of levodopa-induced dyskinesias in Parkinson’s disease. Parkinsons Dis 2012;2012:943159.
19.
Werge T, Elbaek Z, Andersen MB, Lundbaek JA, Rasmussen HB. Cebus apella, a nonhuman primate highly susceptible to neuroleptic side effects, carries the GLY9 dopamine receptor D3 associated
23.
Malik P, Andersen MB, Peacock L. The effects of dopamine D3 agonists and antagonists in a nonhuman primate model of tardive dyskinesia. Pharmacol Biochem Behav 2004;78:805-810.
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