Abstract
The selection and early development of clozapine was based upon its gross behavioural, arousal-inhibiting, sleep-promoting, and caudate spindle-prolonging properties. Compared to classical neuroleptics, clozapine causes only a short-lasting elevation of plasma prolactin levels, elevates both striatal homovanillic acid and dopamine content, is devoid of marked apomorphine-inhibitory or cataleptogenic activity and fails to induce supersensitivity of striatal dopaminergic systems after chronic administration. Clozapine's intrinsic anticholinergic activity, while stronger than that of other neuroleptic agents, does not appear to underlie either its failure to induce tardive dyskinesias or its superior antipsychotic activity. Furthermore, the overlap between clozapine and several classical neuroleptics with regard to alpha-adrenergic-, serotonin- and histamine-blocking activity makes it unlikely that one or more of these properties is the key to its atypical characteristics. More recent findings show that clozapine and classical neuroleptics differ with regard to their indirect effects on nigral GABA-ergic mechanisms implicated in the induction of tardive dyskinesias and, possibly in keeping with this, that clozapine and similar agents exhibit preferential blockade of D-1 dopamine receptors in the whole animal. Such an action of clozapine in man could well explain both its low EPS liability and, in some subjects, its superior antipsychotic activity.
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References
Andersen PH (1988) Comparison of the pharmacological characteristics of [3-H]SCH 23390 binding to dopamine receptors in vivo in mouse brain. Eur J Pharmacol 146:113–120
Andersen PH, Nielsen EB, Gronvald FC, Braestrup C (1986) Some atypical neuroleptics inhibit [3-H]SCH 23390 binding in vivo. Eur J Pharmacol 120:143–144
Angst J, Bente D, Berner P, Heiman H, Helmchen H, Hippius H (1971) Das klinische Wirkungsbild von Clozapin (Untersuchung mit dem AMP-System). Pharmakopsychiatry 4:201–211
Arnt J, Scheel-Krüger J (1980) Intranigral GABA antagonists produce dopamine-independent biting in rats. Eur J Pharmacol 62:51–61
Arnt J, Hyttel J, Bach-Lauritsen T (1986) Further studies on the mechanism behind scopolamine-induced reversal of anti-stereotypic and cataleptogenic effect of neuroleptics in rats. Acta Pharmacol Toxicol 59:319–324
Balsara JJ, Jadhav JH, Chandorkar AG (1979a) Effects of drugs influencing central serotoninergic mechanisms on haloperidol-induced catalepsy. Psychopharmacology 62:67–69
Balsara JJ, Jadhav JH, Muley MP, Chandorkar AG (1979b) Effect of drugs influencing central 5-hydroxytryptaminergic mechanisms on morphine-induced catalepsy in the rat. J Pharm Pharmacol 31:255–257
Bowers MB, Rozitis A (1976) Brain homovanillic acid: changes over time with antipsychotic drugs. Eur J Pharmacol 39:109–115
Boyson SJ, McGonigle P, Molinoff PB (1986) Quantitative autoradiographic localisation of the D-1 and D-2 subtypes of dopamine receptors in rat brain. J Neurosci 6:3177–3188
Boyson SJ, McGonigle P, Luthin GR, Wolfe BB, Molinoff PB (1988) Effects of chronic administration of neuroleptic and anticholinergic agents on the densities of D-2 dopamine and muscarinic cholinergic receptors in rat striatum. J Pharmacol Exp Ther 244:987–993
Broekkamp CL, LePichon M, Lloyd KG (1984) Akinesia after locally-applied morphine near the nucleus raphe pontis of the rat. Neurosci Lett 50:313–318
Broekkamp CLE, Oosterlo SK, Berendsen HHG, van Delft AML (1988) Effect of metergoline, fenfluramine and 8-OHDPAT on catalepsy induced by haloperidol or morphine. Naunyn-Schmiedeberg's Arch Pharmacol 338:191–195
Carter CJ, Pycock CJ (1977) Possible importance of 5-hydroxytryptamine in neuroleptic-induced catalepsy in rats. Br J Pharmacol 60:267P
Carvey PM, Hitri A, Goetz CG, Tanner CM, Klawans HL (1988) Concurrent treatment with benztropine and haloperidol attenuates development of behavioral hypersensitivity but not dopamine receptor proliferation. Life Sci 42:2207–2215
Chiodo LA, Bunney BS (1983) Typical and atypical neuroleptics: differential effects of chronic administration on the activity of A9 and A10 midbrain dopaminergic neurons. J Neurosci 3:1607–1619
Chiodo LA, Bunney BS (1985) Possible mechanisms by which repeated clozapine administration differentially affects the activity of two subpopulations of midbrain dopamine neurons. J Neurosci 5:2539–2544
Creese I, Burt DR, Snyder S (1976) Dopamine receptor binding predicts clinical and pharmacological potencies of antischizophrenic drugs. Science 192:481–483
Coward DM (1982) Classical and non-classical neuroleptics induce supersensitivity of nigral GABA-ergic mechanisms in the rat. Psychopharmacology 78:180–184
De Keyser J, Claeys A, De Backer J-P, Ebinger G, Roels F, Vauquelin G (1988) Autoradiographic localization of D-1 and D-2 receptors in the human brain. Neurosci Lett 91:142–147
Farde L, Wiesel F-A, Halldin C, Sedvall G (1988a) Central D2-dopamine receptor occupancy in schizophrenic patients treated with anti-psychotic drugs. Arch Gen Psychiatry 45:71–76
Farde L, Wiesel F-A, Nordstrom A-L, Sedvall G (1988b) PET examination of human D1- and D2-dopamine receptor characteristics. Abstracts of the XVIth C.I.N.P. Congress, Munich. Psychopharmacology [Suppl] 96:79
Frey JM, Ticku MK, Huffman RD (1987) GABAergic supersensitivity within the pars reticulata of the rat substantia nigra following chronic haloperidol administration. Brain Res 425:73–84
Gale K (1980) Chronic blockade of dopamine receptors by antischizophrenic drugs enhances GABA binding in substantia nigra. Nature 283:569–570
Gerlach J (1977) The relationship between parkinsonism and tardive dyskinesia. Am J Psychiatry 143:781–784
Gross H, Langer E (1966) Das Wirkungsprofil eines chemisch neuartigen. Breitbandneuroleptikums der Dibenzodiazepingruppe. Wien Med Wochenschr 116:814–816
Gunne L-M, Haggstrom J-E (1983) Reduction of nigral glutamic acid decarboxylase in rats with neuroleptic-induced dyskinesia. Psychopharmacology 81:191–194
Gunne L-M, Haggstrom J-E, Sjoquist B (1984) Association with persistent neuroleptic-induced dyskinesia of regional changes in brain GABA synthesis. Nature 309:347–349
Hess EJ, Norman AB, Creese I (1988) Chronic treatment with dopamine receptor antagonists: behavioural and pharmacological effects on D-1 and D-2 dopamine receptors. J Neurosci 8:2361–2370
Imperato A, Angelucci L (1988) Effects of the atypical neuroleptics clozapine and fluperlapine on the in vivo dopamine release in the dorsal striatum and in the prefrontal cortex. Abstracts of the XVIth C.I.N.P. Congress, Munich. Psychopharmacology [Suppl] 96:79
Kane J, Honigfeld G, Singer J, Meltzer HY (1988) Clozapine for the treatment-resistant schizophrenic. Arch Gen Psychiatry 45:789–796
Klawans HL (1973) The pharmacology of tardive dyskinesias. Am J Psychiatry 130:82–86
Maidment NT, Marsden CA (1987) Repeated atypical neuroleptic administration: effects on central dopamine metabolism monitored by in vivo voltammetry. Eur J Pharmacol 136:141–149
Mao CC, Cheney DL, Marco E, Revuelta A, Costa E (1977) Turnover times of gamma-butyric acid and acetylcholine in nucleus caudatus, nucleus accumbens, globus pallidus and substantia nigra: effects of repeated administration of haloperidol. Brain Res 132:375–379
Meltzer HY, Daniels S, Fang VS (1975) Clozapine increases rat serum prolactin levels. Life Sci 17:339–342
Meltzer HY, Nash JF, Koenig JI, Gudelsky GA (1986) Clozapine: neuroendocrine studies of an atypical neuroleptic. Clin Neuropharmacol [Suppl 4] 9:316–318
Memo M, Kleinman JE, Hanbauer I (1983) Coupling of dopamine D-1 recognition sites with adenylate cyclase in nucleus accumbens and caudatus of schizophrenics. Science 221:1304–1307
Nauta WHJ, Smith GP, Faull RLM, Domesick VB (1978) Efferent connections and nigral afferents of the nucleus accumbens septi in the rat. Neuroscience 3:385–401
Olianas MC, De Montis GM, Mulas G, Tagliamonte A (1978) The striatal dopaminergic function is mediated by the inhibition of a nigral, non-dopaminergic system via a striato-nigral GABAergic pathway. Eur J Pharmacol 49:233–241
Redgrave P, Dean P, Donohoe TP, Pope SG (1980) Superior colliculus lesions selectively attenuate apomorphine-induced oral stereotypy: a possible role for the nigrotectal pathway. Brain Res 196:541–546
Sarnek J, Baran L (1975) The effect of 5-hydroxytryptamine synthesis inhibitors on neuroleptic-induced catalepsy in rats. Arch Immunol Ther Exp 23:511–516
Sayers AC, Buerki H-R, Ruch W, Asper H (1975) Neuroleptic-induced hypersensitivity of striatal dopamine receptors in the rat as a model of tardive dyskinesias. Effects of clozapine, loxapine and chlorpromazine. Psychopharmacologia 41:97–104
Sayers AC, Buerki H-R, Ruch W, Asper H (1976) Anticholinergic properties of antipsychotic drugs and their relation to extrapyramidal side-effects. Psychopharmacology 51:15–22
Scheel-Krüger J, Magelund G, Olianas M, Arnt J, Christensen AV (1981) GABA: an important moderator and mediator of dopamine-dependent behaviours. Adv Biosci 31:31–41
Seeman P, Lee T, Chau-Wong M, Wong K (1976) Antipsychotic drug doses and neuroleptic/dopamine receptors. Nature 261:717–719
Shippenberg TS, Herz A (1988) Motivational effects of opioids: influence of D-1 versus D-2 receptor antagonists. Eur J Pharmacol 151:233–242
Snyder S, Greenberg D, Yamamura HI (1974) Antischizophrenic drugs and brain cholinergic receptors. Arch Gen Psychiatry 31:58–61
Stevens JR (1973) An anatomy of schizophrenia? Arch Gen Psychiatry 29:177–189
Stevens JR, Wilson K, Foote W (1974) GABA blockade, dopamine and schizophrenia: experimental studies in the cat. Psychopharmacologia 39:105–119
Stille G, Lauener H, Eichenberger E (1971) The pharmacology of 8-chloro-11-(4-methyl-1-piperazinyl)-5H-dibenzo[b,e][1,4]diazepine (clozapine). Il Pharmacol 26:603–625
Stoof JC, Verheijden PFHM (1986) D-2 receptor stimulation inhibits cyclic AMP formation brought about by D-1 receptor stimulation in rat neostriatum but not nucleus accumbens. Eur J Pharmacol 129:205–206
Tarsy D, Baldessarini RJ (1977) The pathophysiologic basis of tardive dyskinesias. Biol Psychiatry 12:431–450
Vidali M, Fregnan GB (1979) Effect of different CNS-active drugs on the catalepsy induced by neuroleptics. Curr Ther Res 25:544–556
Waddington JL (1986) Behavioural correlates of the actions of selective dopamine D-1 receptor antagonists: impact of SCH 23390 and SKF 83566, and functionally interactive D-1:D-2 receptor systems. Biochem Pharmacol 35:3661–3667
White FJ, Wang RY (1983) Comparison of the effects of chronic haloperidol treatment on A9 and A10 dopamine neurons in the rat. Life Sci 32:983–993
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Coward, D.M., Imperato, A., Urwyler, S. et al. Biochemical and behavioural properties of clozapine. Psychopharmacology 99 (Suppl 1), S6–S12 (1989). https://doi.org/10.1007/BF00442552
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DOI: https://doi.org/10.1007/BF00442552