[Attenuation of phencyclidine-induced object recognition deficits by the combination of atypical antipsychotic drugs with pimavanserin (ACP 103), a 5-hydroxytryptamine2A receptor inverse agonist.]
>>J Pharmacol Exp Ther. 2009 Oct 28. [Epub ahead of print]
Attenuation of phencyclidine-induced object recognition deficits by the combination of atypical antipsychotic drugs with pimavanserin (ACP 103), a 5-hydroxytryptamine2A receptor inverse agonist.
Snigdha S, Horiguchi M, Li Z, Huang M, Shahid M, Neill JC, Meltzer HY.
1 Vanderbilt Medical Center;
Sub-chronic administration of the NMDA 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 M10097, would potentiate sub-effective doses of atypical antipsychotic drugs (APDs) to reverse the NOR deficits. Methods: Female rats received vehicle or PCP (2 mg/kg bid) for 7 days, followed by 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 adminstered alone, or in combination with pimavanserin or M100907, prior to NOR testing. The exploration times of objects during 3 min acquisition and retention trials, separated by a 1 min interval, were compared by ANOVA. Results: 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. Co-administration 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-HT(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.<<
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