Schizophrenia Research
Volume 77, Issue 2 , Pages 189-199 , 15 September 2005

Contrasting loxapine to its isomer isoloxapine—the critical role of in vivo D2 blockade in determining atypicality

  • Sridhar Natesan

      Affiliations

    • Schizophrenia-PET program, Centre for Addiction and Mental Health, 250 College Street, Toronto, Ontario, Canada, M5T 1R8
    • ,
  • Suzi VanderSpek

      Affiliations

    • Schizophrenia-PET program, Centre for Addiction and Mental Health, 250 College Street, Toronto, Ontario, Canada, M5T 1R8
    • ,
  • José N. Nobrega

      Affiliations

    • Neuroimaging Research Section, Centre for Addiction and Mental Health, 250 College Street, Toronto, Ontario, Canada, M5T 1R8
    • Department of Pharmacology, 1 King's College Circle, University of Toronto, Toronto, Ontario, Canada, M5S 1A8
    • ,
  • Robert A. McClelland

      Affiliations

    • Department of Chemistry, 80 St. George Street, University of Toronto, Toronto, Ontario, Canada, M5S 3H6
    • ,
  • Shitij Kapur

      Affiliations

    • Schizophrenia-PET program, Centre for Addiction and Mental Health, 250 College Street, Toronto, Ontario, Canada, M5T 1R8
    • Department of Psychiatry, University of Toronto, 8th Floor, 250 College Street, Toronto, Ontario, Canada, M5T 1R8
    • Corresponding Author InformationCorresponding author. Centre for Addiction and Mental Health, ARF Site, 33 Russell Street, Toronto, Ontario, Canada, M5S 2S1. Tel.: +1 416 979 6890; fax: +1 416 260 4206.

Received 3 December 2004 ,Revised 1 March 2005 ,Accepted 14 March 2005.

References 

  1. Ahlenius S, Hillegaart V. Involvement of extrapyramidal motor mechanisms in the suppression of locomotor activity by antipsychotic drugs: a comparison between the effects produced by pre- and post-synaptic inhibition of dopaminergic neurotransmission. Pharmacol. Biochem. Behav. 1986;24:1409–1415
  2. Bun SS, Voeurng V, Bun H. Interspecies variability and drug interactions of loxapine metabolism in liver microsomes. Eur. J. Drug Metab. Pharmacokinet. 2003;28:295–300
  3. Bymaster FP, Felder CC, Tzavara E, Nomikos GG, Calligaro DO, McKinzie DL. Muscarinic mechanisms of antipsychotic atypicality. Prog. Neuro-psychopharmacol. Biol. Psychiatry. 2003;27:1125–1143
  4. Carta AR, Gerfen CR. Lack of a role for the D3 receptor in clozapine induction of c-fos demonstrated in D3 dopamine receptor-deficient mice. Neuroscience. 1999;90:1021–1029
  5. Cheng Y, Prusoff WH. Relationship between the inhibition constant (Ki) and the concentration of inhibitor which causes 50 percent inhibition (I50) of an enzymatic reaction. Biochem. Pharmacol. 1973;22:3099–3108
  6. Cheung SW, Tang SW, Remington G. Simultaneous quantitation of loxapine, amoxapine and their 7- and 8-hydroxy metabolites in plasma by high-performance liquid chromatography. J. Chromatogr. 1991;564:213–221
  7. Coupet J, Rauh CE. 3H-Spiroperidol binding to dopamine receptors in rat striatal membranes: influence of loxapine and its hydroxylated metabolites. Eur. J. Pharmacol. 1979;55:215–218
  8. DePaulo JR, Ayd FJ. Loxapine: fifteen years' clinical experience. Psychosomatics. 1982;23:261–271
  9. Farde L, Wiesel FA, Halldin C, Sedvall G. Central D2-dopamine receptor occupancy in schizophrenic patients treated with antipsychotic drugs. Arch. Gen. Psychiatry. 1988;45:71–76
  10. Finney DJ. Probit Analysis. third ed.. London: Cambridge University Press; 1971;
  11. Glazer WM. Does loxapine have “atypical” properties? Clinical evidence. J. Clin. Psychiatry. 1999;60(Suppl. 10):42–46
  12. Heel RC, Brogden RN, Speight TM, Avery GS. Loxapine: a review of its pharmacological properties and therapeutic efficacy as an antipsychotic agent. Drugs. 1978;15:198–217
  13. Hoffman DC, Donovan H. Catalepsy as a rodent model for detecting antipsychotic drugs with extrapyramidal side effect liability. Psychopharmacology (Berl.). 1995;120:128–133
  14. Kalkman HO, Neumann V, Hoyer D, Tricklebank MD. The role of alpha2-adrenoceptor antagonism in the anti-cataleptic properties of the atypical neuroleptic agent, clozapine, in the rat. Br. J. Pharmacol. 1998;124:1550–1556
  15. Kapur S, Seeman P. Does fast dissociation from the dopamine D(2) receptor explain the action of atypical antipsychotics?: a new hypothesis. Am. J. Psychiatry. 2001;158:360–369
  16. Kapur S, Zipursky R, Remington G, Jones C, McKay G, Houle S. PET evidence that loxapine is an equipotent blocker of 5-HT2 and D2 receptors: implications for the therapeutics of schizophrenia. Am. J. Psychiatry. 1997;154:1525–1529
  17. Kapur S, Zipursky RB, Remington G. Clinical and theoretical implications of 5-HT2 and D2 receptor occupancy of clozapine, risperidone, and olanzapine in schizophrenia. Am. J. Psychiatry. 1999;156:286–293
  18. Kapur S, Zipursky R, Jones C, Remington G, Houle S. Relationship between dopamine D(2) occupancy, clinical response, and side effects: a double-blind PET study of first-episode schizophrenia. Am. J. Psychiatry. 2000;157:514–520
  19. Kapur S, Langlois X, Vinken P, Megens AA, De Coster R, Andrews JS. The differential effects of atypical antipsychotics on prolactin elevation are explained by their differential blood–brain disposition: a pharmacological analysis in rats. J. Pharmacol. Exp. Ther. 2002;302:1129–1134
  20. Kapur S, McClelland RA, VanderSpek SC, Wadenberg ML, Baker G, Nobrega J, et al. Increasing D2 affinity results in the loss of clozapine's atypical antipsychotic action. Neuroreport. 2002;13:831–835
  21. Kapur S, VanderSpek SC, Brownlee BA, Nobrega JN. Antipsychotic dosing in preclinical models is often unrepresentative of the clinical condition: a suggested solution based on in vivo occupancy. J. Pharmacol. Exp. Ther. 2003;305:625–631
  22. Kapur S, Natesan S, Remington G. The newer antipsychotics: underlying mechanisms and the new clinical realities. Curr. Opin. Psychiatry. 2004;17:115–121
  23. Leucht S, Pitschel-Walz G, Engel RR, Kissling W. Amisulpride, an unusual “atypical” antipsychotic: a meta-analysis of randomized controlled trials. Am. J. Psychiatry. 2002;159:180–190
  24. Leysen JE, Janssen PM, Schotte A, Luyten WH, Megens AA. Interaction of antipsychotic drugs with neurotransmitter receptor sites in vitro and in vivo in relation to pharmacological and clinical effects: role of 5HT2 receptors. Psychopharmacology (Berl.). 1993;112:S40–S54
  25. Liu IS, Seeman P, Sanyal S, Ulpian C, Rodgers-Johnson PE, Serjeant GR, et al. Dopamine D4 receptor variant in Africans, D4valine194glycine, is insensitive to dopamine and clozapine: report of a homozygous individual. Am. J. Med. Genet. 1996;61:277–282
  26. McAllister KH, Rey B. Clozapine reversal of the deficits in coordinated movement induced by D2 receptor blockade does not depend upon antagonism of alpha2 adrenoceptors. Naunyn-Schmiedeberg's Arch. Pharmacol. 1999;360:603–608
  27. Meltzer HY, Goode DJ, Schyve PM, Young M, Fang VS. Effect of clozapine on human serum prolactin levels. Am. J. Psychiatry. 1979;136:1550–1555
  28. Meltzer HY, Matsubara S, Lee JC. Classification of typical and atypical antipsychotic drugs on the basis of dopamine D-1, D-2 and serotonin2 pKi values. J. Pharmacol. Exp. Ther. 1989;251:238–246
  29. Meltzer HY, Matsubara S, Lee JC. The ratios of serotonin2 and dopamine2 affinities differentiate atypical and typical antipsychotic drugs. Psychopharmacol. Bull. 1989;25:390–392
  30. Paxinos G, Watson C. The rat brain in stereotaxic coordinates, seconded. New York: Academic Press; 1986;
  31. Robertson GS, Matsumura H, Fibiger HC. Induction patterns of Fos-like immunoreactivity in the forebrain as predictors of atypical antipsychotic activity. J. Pharmacol. Exp. Ther. 1994;271:1058–1066
  32. Schmutz J. Neuroleptic piperazinyl-dibenzo-azepines. Chemistry and structure–activity relationships. Arzneimittelforschung. 1975;25:712–720
  33. Schotte A, Janssen PF, Bonaventure P, Leysen JE. Endogenous dopamine limits the binding of antipsychotic drugs to D3 receptors in the rat brain: a quantitative autoradiographic study. Histochem. J. 1996;28:791–799
  34. Seeman P. Antipsychotic drugs, dopamine receptors, and schizophrenia. Clin. Neurosci. Res. 2001;1:53–60
  35. Singh AN, Barlas C, Singh S, Franks P, Mishra RK. A neurochemical basis for the antipsychotic activity of loxapine: interactions with dopamine D1, D2, D4 and serotonin 5-HT2 receptor subtypes. J. Psychiatry Neurosci. 1996;21:29–35
  36. Stockmeier CA, DiCarlo JJ, Zhang Y, Thompson P, Meltzer HY. Characterization of typical and atypical antipsychotic drugs based on in vivo occupancy of serotonin2 and dopamine2 receptors. J. Pharmacol. Exp. Ther. 1993;266:1374–1384
  37. Sumiyoshi T, Kido H, Sakamoto H, Urasaki K, Suzuki K, Yamaguchi N, et al. Time course of dopamine1,2 and serotonin2 receptor binding of antipsychotics in vivo. Pharmacol. Biochem. Behav. 1994;49:165–169
  38. Svensson TH. Alpha-adrenoceptor modulation hypothesis of antipsychotic atypicality. Prog. Neuro-psychopharmacol. Biol. Psychiatry. 2003;27:1145–1158
  39. Wadenberg ML, Hicks PB. The conditioned avoidance response test re-evaluated: is it a sensitive test for the detection of potentially atypical antipsychotics?. Neurosci. Biobehav. Rev. 1999;23:851–862
  40. Wadenberg ML, Hicks PB, Richter JT, Young KA. Enhancement of antipsychoticlike properties of raclopride in rats using the selective serotonin2A receptor antagonist MDL 100,907. Biol. Psychiatry. 1998;44:508–515
  41. Wadenberg ML, Kapur S, Soliman A, Jones C, Vaccarino F. Dopamine D2 receptor occupancy predicts catalepsy and the suppression of conditioned avoidance response behavior in rats. Psychopharmacology (Berlin). 2000;150:422–429
  42. Wadenberg ML, Browning JL, Young KA, Hicks PB. Antagonism at 5-HT(2A) receptors potentiates the effect of haloperidol in a conditioned avoidance response task in rats. Pharmacol. Biochem. Behav. 2001;68:363–370
  43. Wadenberg ML, Soliman A, VanderSpek SC, Kapur S. Dopamine D(2) receptor occupancy is a common mechanism underlying animal models of antipsychotics and their clinical effects. Neuropsychopharmacology. 2001;25:633–641

PII: S0920-9964(05)00119-2

doi: 10.1016/j.schres.2005.03.009

Schizophrenia Research
Volume 77, Issue 2 , Pages 189-199 , 15 September 2005

Article Tools

* Image Usage & Resolution