The role of serotonin (5-HT)7 receptor antagonism in the actions of atypical antipsychotic drugs (APDs) e.g. amisulpride, clozapine, and lurasidone, if any, is uncertain. We examined the ability of 5-HT7 receptor antagonism alone and as a component of amisulpride and lurasidone to reverse deficits in rat novel object recognition (NOR) produced by subchronic treatment with the NMDA receptor antagonist, phencyclidine (PCP), and of supplemental 5-HT7 antagonism to augment the inability of sulpiride, haloperidol and LY379268, a mGluR2/3 agonist, which lack 5-HT7 antagonism, to reverse the NOR deficit. The 5-HT7 receptor antagonist, SB269970 (0.1-1mg/kg) dose-dependently reversed PCP-induced NOR deficits. Additionally, the ability of lurasidone (0.1mg/kg) and amisulpride (3mg/kg) to reverse this deficit was blocked by co-treatment with the 5-HT7 receptor agonist, AS19 (5-10mg/kg) which did not affect NOR in naive rats. Sulpiride, a less potent 5-HT7 antagonist than amisulpride, did not itself improve the PCPinduced NOR deficit. However, a sub-effective dose of SB269970 (0.1mg/kg) in combination with sub-effective doses of lurasidone (0.03mg/kg), amisulpride (1mg/kg), or sulpiride (20mg/kg), also reversed the PCP-induced NOR deficit. Pimavanserin, a 5-HT2A inverse agonist, LY379268, and haloperidol did not potentiate the ability of sub-effective SB269970 to improve the NOR deficit. Furthermore, the mGluR2/3 antagonist, LY341495, which blocks the effect of clozapine to reverse the NOR deficit, did not block the SB269970-induced amelioration of the NOR deficit. These results suggest 5-HT7 antagonism may contribute to the efficacy of some atypical APDs in the treatment of cognitive impairment in schizophrenia and may itself have some benefit in this regard.
- Received February 25, 2011.
- Revision received May 6, 2011.
- Accepted May 9, 2011.
- The American Society for Pharmacology and Experimental Therapeutics