Abstract
Accumulating evidence suggests that antipsychotics (APs) that lead to sustained blockade of dopamine D2 receptors are more likely to induce acute extrapyramidal side effects (EPS) compared to APs that only occupy D2 receptors transiently. It is unclear, however, whether a similar relationship exists for long-term AP-induced motoric side effects like tardive dyskinesia (TD). The objective of this study was to ascertain whether transient (via daily subcutaneous (s.c.) injections) vs continuous (via osmotic minipump) AP-induced D2 receptor occupancy differentially affects the development of haloperidol-induced vacuous chewing movements (VCMs), an animal model of TD. Six groups of 12 rats received 0.1, 0.25, or 1 mg/kg of haloperidol or vehicle (n=36) via osmotic minipump (to provide within-day sustained) or daily s.c. injection (within-day transient) for 8 weeks. VCMs were measured on a weekly basis and D2 occupancy levels were measured in vivo using [3H]-raclopride at the end of the experiment. Minipump-treated rats developed HAL dose-dependent D2 occupancies of 0.1 mg/kg/day (57%), 0.25 mg/kg/day (70%), and 1 mg/kg/day (88%). S.C.-treated rats also developed HAL dose-dependent D2 occupancies of 0.1 mg/kg/day (83% peak, 3% trough), 0.25 mg/kg/day (89% peak, 0% trough), and 1 mg/kg/day (94% peak, 17% trough). A total of 43% of rats given 0.25 and 1 mg/kg/day of HAL via minipump developed high VCMs compared to only 8% of the rats given the same doses via daily s.c. injections. The 0.1 mg/kg dose did not give rise to VCMs beyond vehicle levels regardless of the route of administration. These findings support the contention that D2 occupancy levels induced by chronic HAL must be high and sustained through the day before significant risk of VCMs, and perhaps also TD, emerges.
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References
American Psychiatric Association (1994). Diagnostic and Statistical Manual of Mental Disorders: Fourth Addition. Washington, DC: American Psychiatric Press.
Andreassen OA, Jorgensen HA (1994). Tardive dyskinesia: behavioural effects of repeated intracerebroventricular haloperidol injections in rats do not confirm the kindling hypothesis. Pharmacol Biochem Behav 49: 309–312.
Andreassen OA, Jorgensen HA (2000). Neurotoxicity associated with neuroleptic-induced oral dyskinesias in rats: implications for tardive dyskinesia? Prog Neurobiol 61: 525–541.
Bloomquist J, King E, Wright A, Mytilineou C, Kimura C, Castagnoli K et al (1994). 1-Methyl-4-phenylpyridinium-like neurotoxicity of a pyridinium metabolite derived from haloperidol: cell culture and neurotransmitter uptake studies. J Pharmacol Exp Ther 270: 822–830.
Cadet JL, Lohr JB (1989. Possible involvement of free radicals in neuroleptic-induced movement disorders. Evidence from treatment with vitamin E. Ann NY Acad Sci 570: 176–185.
Carpenter Jr WT, Conley R, Kirkpatrick B (2000). On schizophrenia and new generation drugs. Neuropsychopharmacology 22: 660–664.
Casey DE, Keepers GA (1988). Neuroleptic side effects: acute extrapyramidal syndromes and tardive dyskinesia. Psychopharmacol Ser 5: 74–93.
Egan MF, Hurd Y, Ferguson J, Bachus SE, Hamid EH, Hyde TM (1996). Pharmacological and neurochemical differences between acute and tardive vacuous chewing movements induced by haloperidol. Psychopharmacology 127: 337–345.
Ericson H, Radesater A, Servin E, Magnusson O, Mohringe B (1996). Effects of intermittent and continuous administration of raclopride on motor activity, dopamine turnover and receptor occupancy in the rat. Pharmacol Toxicol 79: 277–286.
Farde L, Nordstrom AL, Wiesel FA, Pauli S, Halldin C, Sedvall G (1992). Positron emission tomographic analysis of central D1 and D2 dopamine occupancy in patients treated with classical neuroleptics and clozapine: relation to extrapyramidal side effects. Arch Gen Psychiatry 49: 538–544.
Galili-Mosberg R, Gil-Ad I, Weizman A, Melamed E, Offen D (2000). Haloperidol-induced neurotoxicity—possible implications for tardive dyskinesia. J Neural Transm 107: 479–490.
Glenthoj B (1993). Persistent vacuous chewing in rats following neuroleptic treatment: relationship with dopaminergic and cholinergic function. Psychopharmacology 113: 157–166.
Glenthoj B, Hemmingsen R, Allerup P, Bolwig T (1990). Intermittent versus continuous neuroleptic treatment in a rat model. Eur J Pharmacol 13: 275–286.
Gao XM, Sakai K, Tamminga CA (1998). Chronic olanzapine or sertindole treatment results in reduced oral chewing movements in rats compared to haloperidol. Neuropsychopharmacology 19: 428–433.
Hashimoto T, Ross DE, Gao X-M, Medoff DR, Tamminga CA (1998). Mixture in the distribution of haloperidol induced oral dyskinesias in the rat supports an animal model of tardive dyskinesia. Psychopharmacology 137: 107–112.
Iversen SD, Howells RB, Hughes RP (1980). Behavioural consequences of long-term treatment with neuroleptic drugs. Adv Biochem Pharmacol 24: 305–313.
Kane JM, Woerner M, Borenstein M, Wenger J, Liebaman J (1986). Integrating incidence and prevalence of tardive dyskinesia. Psychopharmacol Bull 22: 254–258.
Kapur S, Remington G (2001a). Dopamine D(2) receptors and their role in atypical antipsychotic action: still necessary and may even be sufficient. Biol Psychiatry 50: 873–883.
Kapur S, Seeman P (2001). Does fast dissociation from the dopamine D2 receptor explain the action of atypical antipsychotics?: a new hypothesis. Am J Psychiatry 158: 360–369.
Kapur S, Zipursky R, Jones C, Remington G, Houle S (2000a). Relationship between dopamine D(2) occupancy, clinical response effects: a double-blind PET study of first-episode schizophrenia. Am J Psychiatry 157: 514–520.
Kapur S, Zipursky R, Jones C, Shammi CS, Remington G, Seeman P (2000b). A positron emission tomography study of quetiapine in schizophrenia: a preliminary finding of an antipsychotic effect with only transiently high dopamine D2 receptor occupancy. Arch Gen Psychiatry 57: 553–559.
Kapur S, Wadenberg ML, Remington G (2000c). Are animal studies of antipsychotics appropriately dosed? Lessons from the bedside to the bench. Can J Psychiatry 45: 241–246.
Kapur S, Zipursky R, Remington G (1999). Clinical and theoretical implications of 5-HT2 and D2 receptor occupancy of clozapine, risperidone, and olanzapine in schizophrenia. Am J Psychiatry 156: 286–293.
Kashihara K, Sato M, Fujiwara Y et al (1986). Effects of intermittent and continuous haloperidol administration on the dopaminergic system of the rat brain. Biol Psychiatry 21: 650–656.
Naidu PS, Kulkarni SK (2001). Excitation mechanisms in neuroleptic induced vacuous chewing movements (VCMs): Possible involvement of calcium and nitric oxide. Behav Pharmacol 12: 209–216.
Remington G, Kapur S (2000). Atypical antipsychotics: are some more atypical than others? Psychopharmacology 148: 3–15.
Rupniak NMJ, Jenner P, Marsden CD (1985). Pharmacological characteristics of spontaneous or drug-associated purposeless chewing movements in rats. Psychopharmacology 85: 71–79.
Sagara Y (1998). Induction of reactive oxygen species in neurons by haloperidol. J Neurochem 71: 1002–1012.
Sakai K, Gao X-M, Tamminga CA (2001). Scopolamine fails to diminish chronic haloperidol-induced purposeless chewing in rats. Psychopharmacology 153: 191–195.
Salamone JD, Mayorga AJ, Trevitt JT, Cousins NS, Conlan A, Nowab A (1998). Tremulous jaw movements in rats: a model of Parkinsonian tremor. Prog Neurobiol 56: 591–611.
Sasaki T, Kennedy JL, Nobrega JN (1996). Autoradiographic mapping of mu opioid receptor changes in rat brain after long-term haloperidol treatment: relationship to the development of vacuous chewing movements. Psychopharmacology 128: 97–104.
See RE (1993). Assessment of striatal dopamine and dopamine metabolites increases by microdialysis in haloperidol-treated rats exhibiting oral dyskinesia. Neuropsychopharmacology 9: 101–109.
See RE, Klavis PW (1996). Tolerance and sensitization to the effects of antipsychotic drugs on dopamine transmission. In: Csernansky JE (ed) Antipsychotics. Springer: New York. pp 203–224.
Seeman P (2002). Atypical antipsychotics: mechanism of action. Can J Psychiatry 47: 27–38.
Steinpreis RE, Parret F, Summ RM, Panos JJ (1997). Effects of clozapine and haloperidol on baseline levels of vacuous jaw movements in aged rats. Behav Brain Res 86: 165–169.
Tomlinson AJ, Braddock WD, Benson LM, Oda RP, Naylor S (1995). Preliminary investigations of preconcentration-capillary electrophoresis-mass spectrometry. J Chromatogr B 669: 67–73.
Turrone P, Remington G, Nobrega JN (2002). The vacuous chewing movement (VCM) model of tardive dyskinesia revisited: relationship to D2 receptor occupancy. Neurosci Biobehav Rev 26: 361–380.
Turrone P, Remington G, Nobrega JN (2003). The relationship between D2 receptor occupancy and vacuous chewing movements (VCMs) in the rat. Psychopharmacology 165: 166–171.
Van Harten PN, Hoek HW, Matroos GE, Kahn PR (1998). Intermittent neuroleptic treatment and risk for tardive dyskinesia: Curacao extrapyramidal syndromes study II. Am J Psychiatry 155: 565–567.
Volkow ND, Fowler JS, Wang GL (2002). Role of dopamine in drug reinforcement and addiction in humans: results from imaging studies. Behav Pharmacol 13: 355–366.
Wadenberg ML, Soliman A, Vanderspak SC, Kapur S (2001). Dopamine D(2) receptor occupancy is a common machanism underlying animal models of antipsychotics and their clinical effects. Neuropsyopharmacology 25: 633–641.
Wadenberg ML, Kapur S, Soliman A, Jones C, Vaccarino F (2000). Dopamine D2 receptor occupancy predicts catalepsy and the suppression of conditioned avoidance response behaviour in rats. Psychopharmacology 150: 422–429.
Acknowledgements
Mr Peter Turrone's graduate work is supported by an Ontario Graduate Scholarship and Astra-Zeneca Student Fellowship. This work was supported by grants from Janssen Research Foundation and NARSAD. We thank Steven Mann, Susan C VanderSpek, Barb Brownlee, Lisa Richardson, and Dr Catherine Tenn for their expert technical assistance.
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Turrone, P., Remington, G., Kapur, S. et al. Differential Effects of Within-Day Continuous Vs Transient Dopamine D2 Receptor Occupancy in the Development of Vacuous Chewing Movements (VCMs) in Rats. Neuropsychopharmacol 28, 1433–1439 (2003). https://doi.org/10.1038/sj.npp.1300233
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DOI: https://doi.org/10.1038/sj.npp.1300233
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