The role of 5-[HT.sub.1A] receptors in phencyclidine deficit in rats

Rationale Atypical antipsychotic drugs (APDs), many of which are direct or indirect serotonin [(5-HT).sub.1A] agonists, and tandospirone, a 5-H[T.sub.1A] partial agonist, have been reported to improve cognition in schizophrenia. Objectives and methods We tested the effect of 5-H[T.sub.1A] agonism, a...

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Published in:Psychopharmacology 2012-05, Vol.221 (2), p.205
Main Authors: Horiguchi, M, Meltzer, H.Y
Format: Article
Language:English
Subjects:
Cognition
Evaluation
Haloperidol
Methyl aspartate
Phencyclidine
Schizophrenia
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Summary:Rationale Atypical antipsychotic drugs (APDs), many of which are direct or indirect serotonin [(5-HT).sub.1A] agonists, and tandospirone, a 5-H[T.sub.1A] partial agonist, have been reported to improve cognition in schizophrenia. Objectives and methods We tested the effect of 5-H[T.sub.1A] agonism, alone, and in combination with other psychotropic agents, including the atypical APD, lurasidone, in reversing the deficit in novel object recognition (NOR) induced by subchronic treatment with the non-competitive NMDA receptor antagonist, phencyclidine (PCP) (2 mg/kg, b.i.d., for 7 days). Results Subchronic treatment with PCP induced a persistent NOR deficit. Lurasidone (0.1 mg/kg), a potent 5-[HT.sub.1A] partial agonist, 5-[HT.sub.2A] antagonist, and weaker [D.sub.2] antagonist, tandospirone (0.6 mg/kg), and the selective postsynaptic 5-[HT.sub.1A] agonist, F15599 (0.16 mg/kg), ameliorated the subchronic PCP-induced-NOR deficit. The 5-[HT.sub.1A] antagonist, WAY100635 (0.6 mg/kg), blocked the amelio rating effects of tandospirone and lurasidone. The combination of sub-effective doses of tandospirone (0.2 mg/kg) and lurasidone (0.03 mg kg) also reversed the PCP-induced NOR-deficit. Buspirone, a less potent partial 5-[HT.sub.1A] agonist than tandospirone, was less effective. Co-administration of tandospirone (0.2 mg/kg) and pimavanserin (3 mg/kg), a relatively selective 5-[HT.sub.2A] receptor inverse agonist, did not reverse the effect of sub-chronic PCP on NOR. The [D.sub.2] antagonist, haloperidol, blocked the ameliorating effect of tandospirone on the PCP-induced deficit in NOR. Conclusions These results indicate that 5-[HT.sub.1A] agonism is adequate to ameliorate the PCP-induced impairment in NOR and suggest further study of utilizing the combination of a 5-[HT.sub.1A] agonist and an atypical APD to ameliorate some types of cognitive impairment in schizophrenia. Keywords Phencyclidine * Novel object recognition * Schizophrenia * 5-[HT.sub.1A] * Tandospirone * Lurasidone * F15599 * Buspirone * Cognition
ISSN:0033-3158
DOI:10.1007/s00213-011-2561-4