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

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-HT 2A inverse agonists, pimavanserin and, 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 Ͻ 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.

Prevention of the Phencyclidine-Induced Impairment in Novel Object Recognition in Female Rats by Co-Administration of Lurasidone or Tandospirone, a 5-HT1A Partial Agonist

“…As mentioned above, these results are in agreement with the lack of effectiveness of these drugs to acutely reverse the effects of subchronic PCP on NOR (Grayson et al, 2007;Snigdha et al, 2010). Subchronic treatment with haloperidol also did not reverse the NOR deficit induced by subchronic PCP in mice (Hashimoto et al, 2005;Nagai et al, 2009).…”

“…The results in this study are consistent with the acute reversal studies in which atypical APDs, including lurasidone and the 5-HT 1A agonist, tandospirone, but not pimavanserin or haloperidol, are effective reversing PCPinduced cognitive deficits (Grayson et al, 2007;Snigdha et al, 2010;Horiguchi et al, 2011a, b;Horiguchi and Meltzer, 2012). It is of interest to compare these results from acute reversal studies with studies in mice that showed a subchronic PCP (10 mg/kg)-induced NOR deficit in mice and examined the ability of subsequent subchronic administration of APDs to reverse the impairment (Hashimoto et al, 2005;Hagiwara et al, 2008;Nagai et al, 2009;Tanibuchi et al, 2009).…”

“…Testing was carried out according to a previously validated method (Snigdha et al, 2010). Briefly, all rats were habituated for 1 h to the NOR arena for three consecutive days (days 12-14) before the first NOR test.…”

“…Acute or subchronic administration of PCP, MK-801, or ketamine to rodents produces cognitive impairments that model CIS, eg, novel object recognition (NOR; Neill et al, 2010, Meltzer et al, 2011. Acute administration of atypical APDs (eg, clozapine), but not the typical APD, haloperidol, has been reported to reverse cognitive deficits induced by subchronic PCP treatment in rat NOR (Grayson et al, 2007;Snigdha et al, 2010;Horiguchi et al, 2011a). We recently reported that selective 5-HT 2A inverse agonists (eg, pimavanserin) can potentiate the ability of sub-effective doses of several atypical APDs, including lurasidone, to ameliorate the PCP-induced NOR deficit (Snigdha et al, 2010).…”

“…Acute administration of atypical APDs (eg, clozapine), but not the typical APD, haloperidol, has been reported to reverse cognitive deficits induced by subchronic PCP treatment in rat NOR (Grayson et al, 2007;Snigdha et al, 2010;Horiguchi et al, 2011a). We recently reported that selective 5-HT 2A inverse agonists (eg, pimavanserin) can potentiate the ability of sub-effective doses of several atypical APDs, including lurasidone, to ameliorate the PCP-induced NOR deficit (Snigdha et al, 2010). However, there are no reports that show a preventive effect of typical or atypical APDs.…”