Attenuation of phencyclidine-induced object recognition deficits by the combination of atypical antipsychotic drugs and pimavanserin (ACP 103), a 5-hydroxytryptamine2A receptor inverse agonist

S. Snigdha, M. Horiguchi, M. Huang, Z. Li, M. Shahid, J. C. Neill, Herbert Y. Meltzer

Research output: Contribution to journalArticle

73 Scopus citations

Abstract

Subchronic administration of the N-methyl-D-aspartate receptor antagonist, phencyclidine (PCP), in rodents has been shown to produce impairment in novel object recognition (NOR), a model of visual learning and memory. We tested the hypothesis that the selective 5-HT2A inverse agonists, pimavanserin and (R)-(+)-α-(2,3-dimethoxyphenyl)-1-[2-(4-fluorophenylethyl]-4- piperidinemethanol (M100907), would potentiate subeffective doses of atypical antipsychotic drugs (APDs) to reverse the NOR deficits. Female rats received vehicle or PCP (2 mg/kg b.i.d.) for 7 days, followed by a 7-day washout. Pimavanserin (3 mg/kg) or M100907 (1 mg/kg) alone, or four atypicial APDs, risperidone (0.05-0.1 mg/kg), melperone (1-3 mg/kg), olanzapine (1-2 mg/kg), or N-desmethylclozapine (1-2 mg/kg), and the typical APD, haloperidol (0.05- 0.1 mg/kg), were administered alone, or in combination with pimavanserin or M100907, before NOR testing. The exploration times of objects during 3-min acquisition and retention trials, separated by a 1-min interval, were compared by analysis of variance. Vehicle-, but not PCP-treated, animals, explored the novel object significantly more than the familiar in the retention trial (p < 0.05-0.01). Pretreatment with the higher doses of the atypical APDs, but not pimavanserin, M100907, or haloperidol alone, reversed the effects of PCP. The effect of risperidone was blocked by haloperidol pretreatment. Coadministration of pimavanserin or M100907, with ineffective doses of the atypical APDs, but not haloperidol, also reversed the PCP-induced deficit in NOR. These results support the importance of 5-hydroxytryptamine2A receptor blockade relative to D2 receptor blockade in the ability of atypicals to ameliorate the effect of subchronic PCP, a putative measure of cognitive dysfunction in schizophrenia.

Original languageEnglish (US)
Pages (from-to)622-631
Number of pages10
JournalJournal of Pharmacology and Experimental Therapeutics
Volume332
Issue number2
DOIs
StatePublished - Feb 2010

ASJC Scopus subject areas

  • Molecular Medicine
  • Pharmacology

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