The Role of 5-Hydroxytryptamine 7 Receptors in the Phencyclidine-Induced Novel Object Recognition Deficit in Rats

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Abstract
The role of 5-hydroxytryptamine (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 N-methyl-d-aspartate receptor antagonist phencyclidine (PCP), and we examined the ability of supplemental 5-HT7 antagonism to augment the inability of sulpiride, haloperidol, and (1R,4R,5S,6R)-4-amino-2-oxabicyclo[3.1.0]hexane-4,6-dicarboxylic acid (LY379268), a metabotropic glutamate receptor (mGluR) 2/3 agonist, which lack 5-HT7 antagonism, to reverse the NOR deficit. The 5-HT7 receptor antagonist, (2R)-1-[(3-hydroxyphenyl)sulfonyl]-2-[2-(4-methyl-1-piperidinyl)ethyl]pyrrolidine (SB269970) (0.1–1 mg/kg) dose-dependently reversed PCP-induced NOR deficits. In addition, the ability of lurasidone (0.1 mg/kg) and amisulpride (3 mg/kg) to reverse this deficit was blocked by cotreatment with the 5-HT7 receptor agonist (2S)-(+)-5-(1,3,5-trimethylpyrazol-4-yl)-2-(dimethylamino)tetralin (AS19) (5–10 mg/kg), which did not affect NOR in naive rats. Sulpiride, a less potent 5-HT7 antagonist than amisulpride, did not itself improve the PCP-induced NOR deficit. However, a subeffective dose of SB269970 (0.1 mg/kg) in combination with subeffective doses of lurasidone (0.03 mg/kg), amisulpride (1 mg/kg), or sulpiride (20 mg/kg), also reversed the PCP-induced NOR deficit. Pimavanserin, a 5-HT2A inverse agonist, LY379268, and haloperidol did not potentiate the ability of subeffective SB269970 to improve the NOR deficit. Furthermore, the mGluR2/3 antagonist (2S)-2-amino-2-[(1S,2S)-2-carboxycycloprop-1-yl]-3-(xanth-9-yl)propanoic acid (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.

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