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Dopamine neurochemical profile of atypical antipsychotics resembles that of D-1 antagonists

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Summary

The release and metabolism of dopamine in the mouse caudate-putamen were determined after the oral administration of antipsychotic drugs at doses equal to or sixfold greater than the ED50 dose for their inhibition of apomorphine-induced climbing. Dopamine release was equated with concentrations of 3-methoxytyramine (3-MT) and metabolism was equated with concentrations of dihydroxyphenylacetic acid (DOPAC) and homovanillic acid (HVA) levels. Like the D-1 antagonists SCH 23390 and SKF 83566, most antipsychotic agents with an atypical preclinical profile suggestive of low extrapyramidal symptomatology (CGS 10746B, flumezapine, CL 77328, rimcazole, clozapine, RMI 81582, and fluperlapine) never increased dopamine release and produced variable increases in dopamine metabolism. Other atypical antipsychotics (thioridazine, mesoridazine, melperone) increased dopamine release at only one dose tested but increased dopamine metabolism at most doses. Antipsychotic agents associated with extrapyramidal side effects (setoperone, perlapine, haloperidol, chlorpromazine, and metoclopramide) increased dopamine release and metabolism at almost every dose tested. Thus, atypical antipsychotics increase the metabolism but not release of dopamine at behaviorally effective doses. The resemblance of these minimal effects on dopamine release to those obtained with D-1 antagonists that also have an atypical preclinical profile suggests that a mechanism related to D-1 receptor antagonism may contribute to the action of atypical antipsychotics.

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References

  • Altar CA, O'Neil S, Marshall JF (1984) Sensorimotor impairment and elevated levels of dopamine metabolites in the neostriatum occur rapidly after intranigral injection of 6-hydroxydopamine or gamma-hydroxybutyrate in awake rats. Neuropharmacology 23:309–318

    Google Scholar 

  • Altar CA, Wasley AM, Liebman J, Gerhardt S, Kim H, Welch JJ, Wood PL (1986) CGS 10746B: an atypical antipyschotic candidate that selectively decreases dopamine release at behaviorally effective doses. Life Sci 39:699–705

    Google Scholar 

  • Altar CA, Boyar B, Wood PL (1987) Dopamine autoreceptor agonists including CGS 15855A decrease dopamine release and metabolism in mouse brain. Eur J Pharmacol 134:303–311

    Google Scholar 

  • Andersen PH, Grønvald FC, Jansen JA (1985) A comparison between dopamine-stimulated adenylate cyclase and 3H-SCH 23390 binding in rat striatum. Life Sci 37:1971–1983

    Google Scholar 

  • Andersen 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 D-1 receptor. J Neurochem 47:1822–1831

    Google Scholar 

  • Andersen PH, Nielsen EB, Grønvald FC, Braestrup C (1986) Some atypical neuroleptics inhibit [3H]SCH 23390 binding in vivo. Eur J Pharmacol 120:143–144

    Google Scholar 

  • Bartholini G (1976) Differential effect of neuroleptic drugs on dopamine turnover in the extrapyramidal and limbic system. J Pharm Pharmacol 28:429–433

    Google Scholar 

  • Boyar WC, Altar CA (1987) Modulation of dopamine release by D2 but not D1 receptor agonists and antagonists. J Neurochem 48:824–831

    Google Scholar 

  • Bunney BS, Aghajanian GK (1974) Differentiation between neuroleptic antipsychotic properties and side effects by subgroups of dopaminergic neurons. Psychopharm Bull 10:17–18

    Google Scholar 

  • Burki HR, Ruch W, Asper H (1975) Effects of clozapine, thioridazine, perlapine and haloperidol on the metabolism of the biogenic amines in the brain of the rat. Psychopharmacologia 41:27–33

    Google Scholar 

  • Burki HR (1986) Effects of fluperlapine on dopaminergic systems in rat brain. Psychopharmacology 89:77–84

    Google Scholar 

  • Byck R (1975) Drugs and the treatment of psychiatric disorders. In: Goodman CS, Gilman A (eds) The pharmacological basis of therapeutics. The MacMillan Publishing Co, New York, pp 152–199

    Google Scholar 

  • Ceulemans DL, Gelders Y, Hoppenbrouwers M-L, Reyntjens A, Janssen A (1985) Effect of serotonin antagonism in schizophrenia: a pilot study with setoperone. Psychopharmacology 85:329–332

    Google Scholar 

  • Christensen I, Geismar L, Kirkegaard A, Kirkegaard G (1986) Additional studies on side effects of melperone in long-term therapy for 1–20 years in psychiatric patients. Drug Res 36:855–861

    Google Scholar 

  • Costal B, Naylor RJ, Nohria V (1978) Climbing behavior induced by apomorphine in mice: a potential model for the detection of neuoleptic activity. Eur J Pharmacol 50:39–50

    Article  CAS  PubMed  Google Scholar 

  • Crane GE, Smeets RA (1974) Low incidence of extrapyramidal side effects with thioridazine. Arch Gen Psychiat 30:341–343

    Google Scholar 

  • DiGiulio AM, Groppetti A, Cattabeni F, Galli CL, Maggi A, Algeri S, Ponzio F (1978) Significance of dopamine metabolites in the evaluation of drugs acting on dopaminergic neurons. Eur J Pharmacol 52:201–207

    Google Scholar 

  • Ferris RM, Tang FL, Chang K-J, Russel A (1986) Evidence that the potential antipsychotic agent rimcazole (BW 234U) is a specific, competitive antagonist of sigma sites in brain. Life Sci 38:2329–2337

    Google Scholar 

  • Fuller RW, Mason NR (1986) Flumerzapine, an antagonist of central dopamine and serotinin receptors. Res Comm Chem Pathol Pharmacol 54:23–34

    Google Scholar 

  • Galli CL, Cattabeni F, Eros T, Spano PF (1976) A mass fragmentographic assay of 3-methoxytyramine in rat brain. J Neurochem 27:795–798

    Google Scholar 

  • Galizzi J-P, Fosset M, Romey G, Laduron P, Lazdunski M (1986) Neuroleptics of the diphenylbutylpiperidine series are potent calcium channel inhibitors. Proc Natl Acad Sci USA 83:7513–7517

    Google Scholar 

  • Gerhardt S, Gerber R, Liebman JM (1985) SCH 23390 dissociated from conventional neuroleptics in apomorphine climbing and primate acute dyskinesia models. Life Sci 37:2355–2363

    Google Scholar 

  • Gerhardt S, Liebman JM (1983) Is apomorphine-induced climbing a valid screening procedure for novel antipsychotics? A systematic assessment. The Pharmacologist 25:100

    Google Scholar 

  • Gerlach J, Thorsen K, Fog R (1975) Extrapyramidal reactions and amine metabolites in cerebrospinal fluid during haloperidol and clozapine treatment of schizophrenia patients Psychopharmacologia 40:341–350

    Google Scholar 

  • Goldstein JM, Litwin LC, Sutton EB, Malick JB (1987) D-2 dopamine antagonist-like effects of SCH 23390 on A9 and A10 dopamine neurons. Life Sci 40:1039–1044

    Google Scholar 

  • Gould RJ, Murphy KM, Reynolds IJ, Snyder SH (1983) Antischizophrenic drugs of the diphenylbutylpiperidine type act as calcium channel antagonists. Proc Natl Acad Sci USA 80:5122–5125

    Google Scholar 

  • Greenblatt EN, Coupet J, Rauh E, Szucs-Myers VA (1980) Is dopamine antagonism a requisite for neuroleptic activity? Arch Int Pharmacodyn 248:105–119

    Google Scholar 

  • Groppetti A, Parenti M, Galli LL, Bugatti A, Cattabeni F, di Giulio AM, Racagni G (1978) 3-Methoxytyramine and different neuroleptics: dissociation from HVA and DOPAC. Life Sci 23:1763–1768

    Google Scholar 

  • Huff RM, Adams RN (1980) Dopamine release in n. accumbens and striatum by clozapine: simultaneous monitoring by in vivo electrochemistry. Neuropharmacology 19:587–590

    Google Scholar 

  • Iorio LC, Barnett A, Leitz FH, Houser VP, Korduba CA (1983) SCH 23390, a potential benzazepine antipsychotic with unique interactions on dopaminergic systems. J Pharmacol Exp Ther 226:462–467

    Google Scholar 

  • Kehr W (1981) 3-Methoxytyramine and normetanephrine as indicators of dopamine and noradrenaline release in mouse brain vivo. J Neural Trans 50:165–178

    Google Scholar 

  • Kirkegaard A, Kirkegaard G, Geismar L, Christensen I (1981) Additional studies on side effects of melperone in long-term therapy for 1 to 15 years in psychiatric patients. Drug Res 31:737–740

    Google Scholar 

  • Lane RF, Blaha CD (1986) Electrochemistry in vivo: application to CNS pharmacology. Ann NY Acad Sci 473:47–63

    Google Scholar 

  • Liebman JM, Quinn GP, Lovell RA, Vlattas I, Glenn TM (1983) CGS 10746B, a potential antipsychotic agent: evidence for a novel mode of action. Fed Proc 42:1152

    Google Scholar 

  • Lowry OH, Rosebrough NJ, Farr AL, Randall RJ (1951) Protein measurement with the Folin phenol reagent. J Biol Chem 193:265–275

    CAS  PubMed  Google Scholar 

  • Memo M, Kleinman JE, Hanbauer I (1983) Coupling of dopamine D1 recognition sites with adenylate cyclase in nuclei accumbens and caudatus of schizophrenics. Science 221:1304–1307

    Google Scholar 

  • Neale R, Gerhardt S, Liebman J (1983) Effects of the novel antipsychotics, RMI 81582 and clopipazan, on predictors of extrapyramidal liability in squirrel monkeys. Drug Development Res 3:171–176

    Google Scholar 

  • Pinder RM, Brogden RN, Sawyer PR, Speigt TM, Spencer R, Avery GS (1976) Pinozide: a review of its pharmacological properties and therapeutic uses in psychiatry. Drugs 12:1–40

    Google Scholar 

  • Saller CG, Salama AI (1986) 3-Methoxytyramine accumulation: effects of typical neuroleptics and various atypical compounds. Naunyn-Schmiedeberg's Arch Pharmacol 334:125–132

    Google Scholar 

  • Soares-Da-Silva P (1986) Does brain 3,4-dihydroxyphenylacetic acid reflect dopamine release? J Pharm Pharmacol 39:127–129

    Google Scholar 

  • Stanley M, Wilk S (1979) Striatal DOPAC elevation predicts antipsychotic efficacy of metoclopramide. Life Sci 24:1907–1912

    Google Scholar 

  • Stanley M, Lautin A, Rotrosen J, Gershon S, Kleinberg D (1980) Metoclopramide: antipsychotic efficacy of a drug lacking potency in receptor models. Psychopharmacology 71:219–225

    Google Scholar 

  • Stifle G, Sayers AC, Lauener H, Eicheberger E (1973) 6(4-Methyl-1-piperazinyl)-morphanthridine (perlapine), a new tricylic compound with sedative and sleep-promoting properties. Psychopharmacologica (Berl) 28:325–337

    Google Scholar 

  • Waldmeier PC, Maitre L (1976) On the relevance of preferential increases of mesolimbic versus striatal dopamine turnover for the prediction of antipsychotic activity of psychotropic drugs. J Neurochem 27:589–597

    Google Scholar 

  • Welch JJ, Kim HS, Liebman J (1980) Amphetamine-induced increases in dopaminergic single cell firing rate after haloperidol pretreatment correlation with extrapyramidal side effects. Neuropharmacology: 19:371–377

    Google Scholar 

  • Westerink BHC, Spaan SJ (1982) Estimation of the turnover of 3-methoxytyramine in the rat striatum by HPLC with electrochemical detection: implications for the sequence in the cerebral metabolism of dopamine. J Neurochem 38:342–347

    Google Scholar 

  • Westerink BHC (1984) Sequence and significance of dopamine metabolism in the rat brain. Neurochem 7:221–227

    Google Scholar 

  • Winer BJ (1971) Statistical principles in experimental design. McGraw-Hill, New York

    Google Scholar 

  • Woggon B, Angst J (1984) Antipsychotic efficacy of fluperlapine. Neuropsychobiology 11:116–120

    Google Scholar 

  • Wood PL (1982) A mass fragmentographic assay for dopamine and its metabolites using negative chemical ionization. Biomed Mass Spec 9:302–306

    Google Scholar 

  • Wood PL, McQuade PS, Etienne P, Lal S, Nair NPV (1983a) Differential actions of classical and atypical neuroleptics on mouse nigrostriatal neurons. Prog Neuro-Psychopharmacol Biol Psychiat 7:765–768

    Google Scholar 

  • Wood PL, Nair NPV, Lal S, Etienne P (1983b) Buspirone: a potential atypical neuroleptic. Life Sci 33:269–273

    Google Scholar 

  • Young MA, Meltzer HY (1980) RMI-81,582, a novel antipsychotic drug. Psychopharmacology 67:101–106

    Google Scholar 

  • Zetterström T, Sharp T, Ungerstedt U (1985) Effect of neuroleptic drugs on striatal dopamine release and metabolism in the awake rat studied by intracerebral dialysis. Eur J Pharmacol 106:27–37

    Google Scholar 

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Authors and Affiliations

  1. Neuroscience Research, Pharmaceuticals Division, Ciba-Geigy Corporation, 07901, Summit, NJ, USA

    C. A. Altar, W. C. Boyar, A. Wasley, S. C. Gerhardt, J. M. Liebman & P. L. Wood

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  1. C. A. Altar
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  2. W. C. Boyar
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  3. A. Wasley
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  4. S. C. Gerhardt
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  5. J. M. Liebman
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  6. P. L. Wood
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Altar, C.A., Boyar, W.C., Wasley, A. et al. Dopamine neurochemical profile of atypical antipsychotics resembles that of D-1 antagonists. Naunyn-Schmiedeberg's Arch Pharmacol 338, 162–168 (1988). https://doi.org/10.1007/BF00174864

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  • DOI: https://doi.org/10.1007/BF00174864

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