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Psychopharmacology

, Volume 99, Supplement 1, pp S13–S17 | Cite as

Basic biology of clozapine: electrophysiological and neuroendocrinological studies

  • Gary A. Gudelsky
  • J. Frank Nash
  • Sally A. Berry
  • Herbert Y. Meltzer
Article

Abstract

The effects of clozapine and other purported atypical antipsychotics were compared with those of typical antipsychotics within the neuroendocrine axis of the rat. Atypical antipsychotics (e.g., clozapine, thioridazine, melperone, setoperone and RMI 81582) differed from typical antipsychotics (e.g., haloperidol, chlorpromazine, cis-flupentixol and fluphenazine) in that they produced only a brief elevation in serum concentrations of prolactin but marked increases in serum or plasma concentrations of corticosterone and ACTH. Moreover, atypical antipsychotics, but not typical antipsychotics, acutely increased the activity of tuberoinfundibular dopamine neurons, as judged from the accumulation of DOPA in the median eminence after inhibition of decarboxylase activity. The effects of atypical antipsychotics on tuberoinfundibular dopamine neurons and corticosterone secretion were mimicked by neurotensin. It would appear that atypical antipsychotics elicit unique neuroendocrine responses that differentiate these agents from typical antipsychotic drugs.

Key words

Clozapine Dopamine Prolactin Corticosterone 

References

  1. Anderson PH, Braestrup C (1986) Evidence for different states of the dopamine D1 receptor: clozapine and fluperlapine may preferentially label an adenylate cyclase-coupled state of the D1 receptor. J Neurochem 47:1822–1831Google Scholar
  2. Bjerkenstedt L, Eneroth P, Harnryd C, Sedvall G (1977) Effects of melperone and thiothixene on prolactin levels in cerebrospinal fluid and plasma of psychotic women. Arch Psych Neurol Sci 224:281–293Google Scholar
  3. Blaha CD, Lane RF (1987) Chronic treatment with classical and atypical antipsychotics drugs differentially decreases dopamine release in striatum and nucleus accumbens in vivo. Neurosci Lett 78:188–204Google Scholar
  4. Blaha CD, Phillips AG, Fibiger HC, Lane RF (1987) Neurotensin effects on dopamine release in the striatum and nucleus accumbens: site specificity and mechanisms of action. Neurosci Abstr 13:483Google Scholar
  5. 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 3:1607–1619Google Scholar
  6. Claghorn J, Honigfeld G, Abuzzahab F-S, Want R, Steinbrook R, Tuason V, Kerlman G (1987) The risks and benefit of clozapine versus chloropromazine. J Clin Psychopharmacol 7:377–394Google Scholar
  7. Demarest KT, Moore KE (1979) Comparison of dopamine synthesis regulation in the terminals to nigrostriatal, mesolimbic, tuberoinfundibular and tuberohypophyseal neurons. J Neural Transm 46:263–277Google Scholar
  8. Fardé L, Wiesel F-A, Halldin C, Sedvall G (1988) Central D2-dopamine receptor occupancy in schizophrenic patients treated with antipsychotic drugs. Arch Gen Psychiatry 45:71–76Google Scholar
  9. Fuller RW, Snoddy HD (1984) Central dopamine receptors mediating pergolide-induced elevation of serum corticosterone in rats. Neuropharmacology 23:1389–1394Google Scholar
  10. Gudelsky GA (1981) Tuberoinfundibular dopamine neurons and the regulation of prolactin secretion. Psychoneuroendocrinology 6:3–16Google Scholar
  11. Gudelsky GA, Meltzer HY (1988) Activation of tuberoinfundibular dopamine neurons following the acute administration of atypical antipsychotics. Neuropsychopharmacology (in press)Google Scholar
  12. Gudelsky GA, Moore KE (1976) A comparison of the effects of haloperidol on dopamine turnover in the striatum, olfactory tubercle and median eminence of the rat brain. J Pharmacol Exp Ther 202:149–156Google Scholar
  13. Gudelsky GA, Koenig JI, Simonovic M, Koyama T, Ohmori T, Meltzer HY (1987) Differential effects of haloperidol, clozapine and fluperlapine on tuberoinfundibular dopamine neurons and prolactin secretion in the rat. J Neural Transm 68:227–240Google Scholar
  14. Gudelsky GA, Berry SA, Meltzer HY (1988) Neurotensin activates tuberoinfundibular dopamine neurons and increases serum corticosterone concentrations. Neuroendocrinology (in press)Google Scholar
  15. Hand TH, Hu X-T, Wang RY (1987) Differential effects of acute clozapine and haloperidol on the activity of ventral tegmental (A10) and nigrostriatal (A9) dopamine neurons. Brain Res 415:257–269Google Scholar
  16. Hökfelt T, Everitt BJ, Theodorsson, Norheim E, Goldstein M (1984) Occurrence of neurotensin-like immunoreactivity in subpopulations of hypothalamic, mesencephalic and medullary catecholamine neurons. J Comp Neurol 222:543–559Google Scholar
  17. Huff R, Adams RN (1980) Dopamine release in n. accumbens and striatum by clozapine: simultaneous monitoring by in vivo electrochemistry. Neuropharmacology 19:587–590Google Scholar
  18. Imperato A, DiChiara G (1985) Dopamine release and metabolism in awake rats after systemic neuroleptics as studied by transstriatal dialysis. J Neurosci 5:297–306Google Scholar
  19. Kabayama Y, Kato Y, Shimatsu A, Yanarhara N, Imura H (1986) Stimulation by gastrin-releasing peptide, neurotensin, and DN 1417, a novel TRH analog, of dopamine and norepinephrine release from perfused and hypothalamic fragments in vitro. Brain Res 372:394–399Google Scholar
  20. Kane J, Cooper TB, Sachar EJ, Halpern F, Berline S (1981) Clozapine: plasma levels and prolactin response. Psychopharmacology 73:184–187Google Scholar
  21. Kane J, Honigfeld G, Singer J, Meltzer HY, Clozaril Colaborative Study Group (1988) Clozapine to the treatment-resistant schizophrenic: a double-blind comparison versus chlorpromazine/ benztropine. Arch gen Psychiatry 45:789–796Google Scholar
  22. Kiss A, Palkovits M, Antoni F, Eskay R, Skirboll LR (1987) Neurotensin in the rat median eminence: the possible sources of neurotensin-like fibers and varicosities in the external layer. Brain Res 416:129–135Google Scholar
  23. Koenig JL, Mayfield MA, McCann SM, Krulich L (1982) On the prolactin-inhibitory effect of neurotensin. Neuroendocrinology 35:277–281Google Scholar
  24. Lane RF, Blaha CD (1986) Electrochemistry in vivo: application to CNS pharmacology. Ann NY Acad Sci 473:50–69Google Scholar
  25. Lane RF, Blaha CD, Rivet JM (1988) Selective inhibition of mesolimbic dopamine release following chronic administration of clozapine: involvement of alpha1-noradrenergic receptor demonstrated by in vivo volammetry. Brain Res 460:398–401Google Scholar
  26. Meltzer HY, Fang V (1976) The effect of neuroleptics on serum prolactin levels in schizophrenic patients. Arch Gen Psychiatry 30:279–286Google Scholar
  27. Meltzer HY, Daniels S, Fang V (1976) Clozapine increases rat serum prolactin levels. Life Sci 17:339–342Google Scholar
  28. Meltzer HY, Goode DJ, Schyve PM, Young M, Fang VS (1979) Effect of clozapine on human serum prolactin levels. Am J Psychiatry 136:1550–1555Google Scholar
  29. Meltzer HY, Koenig JI, Nash JF, Gudelsky GA (1988) Melperone and clozapine: neuroendocrine effects of atypical neuroleptic drugs. Acta Psychiatry Scand (in press)Google Scholar
  30. Moore KE, Demarest KT (1982) Tuberoifundibular and tuberohypophyseal dopaminergic neurons. In: Ganong WF, Martini L (eds) Frontiers in Neuroendocrinology, vol 7. Raven Press, New York, pp 161–190Google Scholar
  31. Myers RD, Lee TF (1984) Neurotensin perfusion of rat hypothalamus: dissociation of dopamine release from body temperature change. Neuroscience 12:241–253Google Scholar
  32. Povisen UJ, Noung U, Fog R, Gerlach J (1985) Tolerability and therapeutic effect of clozapine: a retrospective investigation of 216 patients treated with clozapine for up to 12 years. Acta Psychiatr Scand 71:176–185Google Scholar
  33. Sachar EJ, Gwen PH, Altman N, Halpern FS, Frantz AG (1976) Use of neuroendocrine techniques in psychopharmacological research. In: Sachar ED (ed) Hormones, behavior and psychopathology. Raven Press, New York, pp 161–176Google Scholar
  34. Tojo K, Kata Y, Kabayama Y, Ohta H, Inoue T, Imura H (1986) Further evidence that central neurotensin inhibits pituitary prolactin secretion by stimulating dopamine release from the hypothalamus. Proc Exp Biol Med 181:517–522Google Scholar
  35. Walters JR, Roth RH (1976) Dopaminergic neurons: a in vivo system for measuring drug interactions with presynaptic receptors. Naunyn-Schmiedeberg's Arch Pharmacol 296:5–14Google Scholar
  36. White FJ, Wang RY (1983) Differential effects of classical and atypical antipsychotic drugs on A9 and A10 dopamine cells. Science 221:1054–1057Google Scholar
  37. Wilk S, Watson E, Stanley ME (1975) Differential senstivity of two dopaminergic structures in rat brain to halperidol and to clozapine. J Pharmacol Exp Ther 195:265–270Google Scholar
  38. Young MA, Meltzer HY (1980) RMI 81582, a novel antipsychotic drug. Psychopharmacology 67:101–106Google Scholar

Copyright information

© Springer-Verlag 1989

Authors and Affiliations

  • Gary A. Gudelsky
    • 1
  • J. Frank Nash
    • 1
  • Sally A. Berry
    • 1
  • Herbert Y. Meltzer
    • 1
  1. 1.Departments of Psychiatry and PharmacologyCase Western Reserve University, School of Medicine, Laboratory of Biological PsychiatryClevelandUSA

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