The role of 5-HT1A receptors in phencyclidine (PCP)-induced novel object recognition (NOR) deficit in rats.
BACKGROUND
Atypical antipsychotic drugs (APDs), many of which are direct or indirect serotonin (5-HT)(1A) agonists, and tandospirone, a 5-HT(1A) partial agonist, have been reported to improve cognition in schizophrenia.


OBJECTIVE
We tested the effect of 5-HT(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(1A) partial agonist, 5-HT(2A) antagonist, and weaker D(2) antagonist, tandospirone (0.6 mg/kg), and the selective post-synaptic 5-HT(1A) agonist, F15599 (0.16 mg/kg), ameliorated the subchronic PCP-induced-NOR deficit. The 5-HT(1A) antagonist, WAY100635 (0.6 mg/kg), blocked the ameliorating 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(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(2A) receptor inverse agonist, did not reverse the effect of sub-chronic PCP on NOR. The D(2) antagonist, haloperidol, blocked the ameliorating effect of tandospirone on the PCP-induced deficit in NOR.


CONCLUSIONS
These results indicate that 5-HT(1A) agonism is adequate to ameliorate the PCP-induced impairment in NOR and suggest further study of utilizing the combination of a 5-HT(1A) agonist and an atypical APD to ameliorate some types of cognitive impairment in schizophrenia.
Division of Psychopharmacology, Vanderbilt University Medical Center, Nashville, TN 37212, USA.
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Horiguchi
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Meltzer
D000818:Animals; D014150:Antipsychotic Agents / Q000008:administration & dosage / Q000494:pharmacology*; D004359:Drug Therapy, Combination; D005260:Female; D006213:Hallucinogens / Q000633:toxicity; D054833:Isoindoles / Q000008:administration & dosage / Q000494:pharmacology; D000069056:Lurasidone Hydrochloride; D010622:Phencyclidine / Q000633:toxicity*; D010879:Piperazines / Q000008:administration & dosage / Q000494:pharmacology; D011743:Pyrimidines / Q000008:administration & dosage / Q000494:pharmacology; D051381:Rats; D020318:Rats, Long-Evans; D044282:Receptor, Serotonin, 5-HT1A / Q000187:drug effects* / Q000378:metabolism; D021641:Recognition, Psychology / Q000187:drug effects; D058825:Serotonin 5-HT1 Receptor Agonists / Q000008:administration & dosage / Q000494:pharmacology*; D012702:Serotonin Antagonists / Q000008:administration & dosage / Q000494:pharmacology; D013844:Thiazoles / Q000008:administration & dosage / Q000494:pharmacology
D014150:Antipsychotic Agents; D006213:Hallucinogens; D054833:Isoindoles; D010879:Piperazines; D011743:Pyrimidines; D058825:Serotonin 5-HT1 Receptor Agonists; D012702:Serotonin Antagonists; D013844:Thiazoles; D044282:Receptor, Serotonin, 5-HT1A; C055267:tandospirone; D010622:Phencyclidine; D000069056:Lurasidone Hydrochloride