Skip to main content
SpringerLink
Log in

Seroquel: biochemical profile of a potential atypical antipsychotic

  • Original Investigations
  • Published:
Psychopharmacology Aims and scope Submit manuscript

Abstract

Seroquel and the atypical antipsychotic clozapine were compared using a number of biochemical measures in rats which are indicative of potential antipsychotic activity and possible extrapyramidal side effect liability. Both in vitro and in vivo, these compounds are low potency D-2 dopamine (DA) receptor antagonists and are relatively more potent 5-HT2 antagonists than typical antipsychotic drugs. Seroquel also exhibited low affinity for D-1 DA receptors in vitro, but D-1 receptor occupancy was not detectable in vivo. Unlike clozapine, Seroquel lacks appreciable activity at either D-1 DA or muscarinic receptors. Following IP administration, both compounds produce similar elevations in DA metabolite concentrations. Following 1 month of daily administration, at doses which produce large increases in striatal DA metabolite concentrations, both Seroquel and clozapine fail, unlike typical antipsychotics, to increase the number of striatal D-2 receptors, but do decrease the number of 5-HT2 receptors in frontal cortex. ICI 204,636 produces a short-lasting increase in plasma prolactin levels, but these increases are much greater than those that are produced by clozapine. One day after 3 weeks of daily administration, tolerance, to the ability of Seroquel to elevate DA metabolite and plasma PRL concentrations is not observed. These biochemical observations are discussed with regard to the atypical profile of Seroquel in behavioral and electrophysiological studies.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Similar content being viewed by others

References

  • Altar CA, Wasley AM, Neale RF, Stone GA (1986) Typical and atypical antipsychotic occupancy of D-2 and S-2 receptors: an autoradiographic analysis in rat brain. Brain Res Bull 16:517–525

    Google Scholar 

  • Anderson G, Rebec GV (1988) Clozapine and haloperidol in the amygdaloid complex: differential effects on dopamine transmission with long-term treatment. Biol Psychiatry 23:497–506

    Google Scholar 

  • Andree TH, Mikuni M, Tong CY, Koeing JI, Meltzer HY (1986) Differential effect of subchronic treatment with various neuroleptic agents on serotonin-2 receptors in rat cerebral cortex. J Neurochem 46:191–197

    Google Scholar 

  • Anger B, Reichert S, Heimpel H (1987) Clozapine-induced agranulocytosis. Blut 55:63–64

    Google Scholar 

  • Asper H, Baggiolini M, Burki HR, Launer H, Ruch W, Stille G (1973) Tolerance phenomena with neuroleptics: catalepsy, apomorphine stereotypies and striatal dopamine metabolism in the rat after single and repeated administration of loxapine and haloperidol. Eur J Pharmacol 22:287–294

    Google Scholar 

  • Casey D (1989) Clozapine: neuroleptic-induced EPS and tardive dyskinesia. Psychopharmacology 99:S47-S53

    Google Scholar 

  • Chang WH, Yeh EK, Hu WH, Tseng YT, Chung MC, Chang HF (1986) Pre-frontal cortex: possible site of antipsychotic action of haloperidol. Biol Psychiatry 21:422–424

    Google Scholar 

  • Chiodo LA, Bunney BS (1985) Possible mechanisms by which repeated clozapine administration differentially affects the activity of two sub-populations of mid-brain dopamine neurons. J Neurosci 5:2539–2544

    Google Scholar 

  • Claghorn J, Honigfeld G, Abuzzahab FS, Wang R, Stienbook A, Tuason V, Klerman G (1987) The risks and benefits of clozapine vs chlorpromazine. J Clin Psychopharmacol 7:377–384

    Google Scholar 

  • Gerlach J, Koppelhu P, Helweg E, Monrad A (1974) Clozapine and haloperidol in a single blind cross-over trial. Therapeutic and biochemical aspects in the treatment of schizophrenia. Acta Psychiatr Scand 50:410–424

    Google Scholar 

  • Goldstein JM, Litwin LC, Sutton EB, Malick JB (1993) Seroquel: electrophysiological profile of a potential atypical antipsychotic. Psychopharmacology 112:293–298

    Google Scholar 

  • Greengrass P, Bremner R (1979) Binding characteristics of3H-prazosin to rat brain alpha-adrenergic receptors. Eur J Pharmacol 55:323–326

    Google Scholar 

  • Griffith RW, Saameli K (1975) Clozapine and agranulocytosis. Lancet 2:657

    Google Scholar 

  • Hall MD, Mesticawy S, Emerit MB, Pritchart L, Harmon M, Gozlan H (1985) [3H]8-Hydroxy-2-(di-n-propylamino), tetralin binding to pre- and postsynaptic 5-hydroxytryptamine sites in various regions of the rat brain. J Neurochem 44:1685–1696

    Google Scholar 

  • Howe JR, Yaksh TL (1986) Characterization of [3H] rauwolsine binding to alpha 2-adrenoceptor sites in the lumbar spinal cord of the cat: comparison to such binding sites in the cat frontal cerebral cortex. Brain Res 368:87–100

    Google Scholar 

  • Kane JM, Honifeld G, Singer J, Meltzer H (1988) Clozapine in treatment-resistant schizophrenics. Psychopharmacol Bull 24:62–86

    Google Scholar 

  • Lee T, Tang SW (1984) Loxapine and clozapine decrease serotonin (S2) but do not elevate dopamine (D2) receptor numbers in the rat brain. Psychiatry Res 12:277–285

    Google Scholar 

  • Leysen JE, Niemegeers CJE, Van Nueten JM, Landuron PM (1982) [3H] Ketanserin (R 41 468), a selective [3H] ligand for serotonin2 receptor binding sites. Binding properties, brain distribution, and functional role. Mol Pharmacol 21:301–314

    Google Scholar 

  • Lieberman JA, Johns CA, Mikane J, Rai K, Pisciotta AV, Saltz BL, Howard A (1988) Clozapine-induced agranulocytosis: non-cross-reactivity with other psychotropic drugs. J Clin Psychiatry 49:271–277

    Google Scholar 

  • Maidment NT, Marsden CA (1982) Repeated atypical neuroleptic administration: Effects on central dopamine metabolism monitored by in vivo voltammetry. Eur J Pharmacol 136:141–147

    Google Scholar 

  • Matsubara S, Meltzer HY (1989) Effects of typical and atypical antipsychotic drugs on 5-HT2 receptor density in rat cerebral cortex. Life Sci 45:1397–1406

    Google Scholar 

  • Matz R, Rick W, Oh D, Thompson H, Gershon S (1974) Clozapine — a potential antipsychotic agent without extrapyramidal manifestation. Curr Ther Res 16:687–695

    Google Scholar 

  • Meltzer HY, Matsubara S, Lee JC (1989) Classification of typical and atypical antipsychotic drugs on the basis of dopamine D-1, D-2 and serotonin2 pKi values. J Pharmacol Exp Ther 25:238–246

    Google Scholar 

  • Migler BM, Warawa EJ, Malick JB (1993) Seroquel: behavioral profile of a potential atypical antipsychotic. Psychopharmacology 112:299–307

    Google Scholar 

  • Saller CF, Salama AI (1984) Rapid automated analysis of biogenic amines and their metabolites using reverse-phase HPLC with electrochemical detection. J Chromatogr 309:287–298

    Google Scholar 

  • Saller CF, Salama AI (1985) Alterations in dopamine metabolism after chronic administration of haloperidol. Neuropharmacology 24:123–129

    Google Scholar 

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

    Google Scholar 

  • Saller CF, Salama AI (1986b) D-1 and D-2 dopamine receptor blockade: interactive effects in vitro and in vivo. J Pharmacol Exp Ther 236:714–720

    Google Scholar 

  • Saller CF, Pacheco MA, Keith RA, Salama AI (1986) 5-Hydroxytryptamine-2 receptor down-regulation after chronic 5-hydroxytryptamine-2 antagonists. Neurosci Abstr 12:311

    Google Scholar 

  • Saller CF, Kreamer LD, Adamovage LA, Salama AI (1989) Dopamine receptor occupancy in vivo: measurement using N-ethoxy-2-ethoxy-1,2-dihydroquinoline (EEDQ). Life Sci 45:917–929

    Google Scholar 

  • Saller CF, Czupryna MJ, Salama AI (1990) 5-HT2 receptor blockade by ICI 169,369 and other 5-HT2 antagonists modulates the effects of D-2 dopamine receptor blockade. J Pharmacol Exp Ther 253:1–9

    Google Scholar 

  • Scatchard G (1949) The attractions of proteins for small molecules and ions. Ann NY Acad Sci 51:660

    Google Scholar 

  • Seeman P (1980) Brain dopamine receptors. Pharmacol Rev 32:229–313

    Google Scholar 

  • Seeman P, Lee T (1975) Antipsychotic drugs: direct correlation between clinical potency and presynaptic action of dopamine neurons. Science 188:1217–1219

    Google Scholar 

  • Shopsin B, Klein H, Aaronson M, Collora M (1979) Clozapine, chlorpromaxine and placebo in newly hospitalized, acutely schizophrenic patients: a controlled, double-blind comparison. Arch Gen Psychiatry 36:657–664

    Google Scholar 

  • Stevens RJ (1973) An anatomy of schizophrenia? Arch Gen D (1983) Neuroleptic-induced extrapyramidal reactions: classification, description and diagnosis. Clin Neuropharmacol 6:59

    Google Scholar 

  • Tarsy D (1983) Neuroleptic-induced extrapyramidal reactions: classification, description and diagnosis. Clin Neuropharmacol 6:59

    Google Scholar 

  • Westerink BHC (1985) Sequence and significance of dopamine metabolism in the rat brain. Neurochem Int 7:221

    Google Scholar 

  • White FJ, Wang RY (1983) Differential effects of classical and atypical antipsychotic drugs on A9 and A10 dopamine neurons. Science 221:1054

    Google Scholar 

  • Wilk S, Stanley M (1978) Clozapine concentrations in brain regions: relationship to dopamine metabolite increase. Eur J Pharmacol 51:101–107

    Google Scholar 

  • Wilmot CA, Szcepanik AM (1989) Effects of acute and chronic treatments with clozapine and haloperidol on serotonin (5-HT2) and dopamine (D2) receptors in the rat brain. Brain Res 487:288–298

    Google Scholar 

Download references

Author information

Author notes

  1. Charles F. Saller

    Present address: Analytical Biological Services Inc., Cornell Business Park, 19801, Wilmington, DE, USA

Authors and Affiliations

  1. Zeneca Pharmaceuticals Group, Department of Pharmacology, 19897, Wilmington, DE, USA

    Charles F. Saller & Andre I. Salama

Authors
  1. Charles F. Saller
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Andre I. Salama
    View author publications

    You can also search for this author in PubMed Google Scholar

Rights and permissions

Reprints and permissions

About this article

Cite this article

Saller, C.F., Salama, A.I. Seroquel: biochemical profile of a potential atypical antipsychotic. Psychopharmacology 112, 285–292 (1993). https://doi.org/10.1007/BF02244923

Download citation

  • Issue Date:

  • DOI: https://doi.org/10.1007/BF02244923

Key words

Search

Navigation