Attenuation of Phencyclidine-Induced Object Recognition Deficits by the Combination of Atypical Antipsychotic Drugs and Pimavanserin (ACP 103), a 5-Hydroxytryptamine 2A Receptor Inverse Agonist S. Snigdha, M. Horiguchi, M. Huang, Z. Li, M. Shahid, J. C. Neill, and H. Y. Meltzer Division of Psychopharmacology, Vanderbilt University School of Medicine, Nashville, Tennessee (S.S., M.Ho., M.Hu., Z.L., H.Y.M.); Organon Schering Plough Laboratories Ltd, Newhouse, Lanarkshire, Glasgow, United Kingdom (M.S.); and School of Pharmacy, University of Bradford, Bradford, United Kingdom (J.C.N.) Received May 19, 2009; accepted September 23, 2009 ABSTRACT Subchronic administration of the N-methyl-D-aspartate recep- tor 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-HT 2A inverse agonists, pimavanserin and (R)-(+)--(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), olanza- pine (1–2 mg/kg), or N-desmethylclozapine (1–2 mg/kg), and the typical APD, haloperidol (0.05– 0.1 mg/kg), were adminis- tered 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 signifi- cantly 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-hydroxytryptamine 2A receptor blockade relative to D 2 receptor blockade in the ability of atypicals to ameliorate the effect of subchronic PCP, a putative measure of cognitive dysfunction in schizophrenia. Deficits in multiple domains of cognition, including visual learning and memory, is a characteristic feature of schizo- phrenia (Meltzer and McGurk, 1999). Atypical antipsychotic drugs (APDs), but less so typical APDs, have usually, but not always, been found to produce significant improvement in some domains of cognition in patients with schizophrenia (Meltzer and McGurk, 1999; Keefe et al., 2007). These classes of APDs differ in the relatively higher affinity for 5-hydroxy- tryptamine (5-HT) 2A compared with dopamine (DA) D 2 re- ceptors of the atypical APDs (Meltzer et al., 1989; Schotte et al., 1996; Meltzer and Huang, 2008). Microdialysis studies in rats have shown that the higher affinity for 5-HT 2A compared with D 2 receptors of the atypical APDs contributes to their ability to enhance cortical and hippocampal DA efflux. This effect has been suggested to be important to their ability to enhance cognitive function in human and rodent models of cognitive impairment (Moghaddam and Bunney, 1990; Ku- roki et al., 1999; Lie ´geois et al., 2002), because hypodopam- inergic activity in the cortex has been postulated to be a major factor in the cognitive impairment of schizophrenia (Goldman-Rakic and Selemon, 1997). Hypoglutamatergic function, particularly in the frontal cortex, has also been suggested to be a major factor in the cognitive impairment of schizophrenia (Coyle, 2006). Acute and subchronic administration of noncompetitive NMDA an- tagonists, e.g., PCP and MK-801, has been reported to pro- duce impairments in visual and learning memory, attention, Article, publication date, and citation information can be found at http://jpet.aspetjournals.org. doi:10.1124/jpet.109.156349. ABBREVIATIONS: APD, atypical antipsychotic drug; DA, dopamine; serotonin (5-HT); NDMC, N-desmethylclozapine; NMDA, N-methyl-D- aspartate; NOR, novel object recognition; PCP, phencyclidine; ACP103, pimavanserin, N-(4-fluorophenylmethyl)-N-(1-methylpiperidin-4-yl)-N'- (4-(2-methylpropyloxy)phenylmethyl) carbamide (2R,3R)-dihydroxybutanedioate (2:1); MK-801, 5H-dibenzo[a,d]cyclohepten-5,10-imine (dizo- cilpine maleate); M100907, (R)-(+)--(2,3-dimethoxyphenyl)-1-[2-(4-fluorophenylethyl]-4-piperidinemethanol. 0022-3565/10/3322-622–631$20.00 THE JOURNAL OF PHARMACOLOGY AND EXPERIMENTAL THERAPEUTICS Vol. 332, No. 2 Copyright © 2010 by The American Society for Pharmacology and Experimental Therapeutics 156349/3548683 JPET 332:622–631, 2010 Printed in U.S.A. 622 at ASPET Journals on January 10, 2017 jpet.aspetjournals.org Downloaded from