The role of 5-hydroxytryptamine 7 receptors in the phencyclidine-induced novel object recognition deficit in rats.
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-HT(7) 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-HT(7) antagonism to augment the inability of sulpiride, haloperidol, and (1R,4R,5S,6R)-4-amino-2-oxabicyclo3.1.0hexane-4,6-dicarboxylic acid (LY379268), a metabotropic glutamate receptor (mGluR) 23 agonist, which lack 5-HT(7) antagonism, to reverse the NOR deficit. The 5-HT(7) receptor antagonist, (2R)-1-(3-hydroxyphenyl)sulfonyl-2-2-(4-methyl-1-piperidinyl)ethylpyrrolidine (SB269970) (0.1-1 mgkg) dose-dependently reversed PCP-induced NOR deficits. In addition, the ability of lurasidone (0.1 mgkg) and amisulpride (3 mgkg) to reverse this deficit was blocked by cotreatment with the 5-HT(7) receptor agonist (2S)-()-5-(1,3,5-trimethylpyrazol-4-yl)-2-(dimethylamino)tetralin (AS19) (5-10 mgkg), which did not affect NOR in naive rats. Sulpiride, a less potent 5-HT(7) antagonist than amisulpride, did not itself improve the PCP-induced NOR deficit. However, a subeffective dose of SB269970 (0.1 mgkg) in combination with subeffective doses of lurasidone (0.03 mgkg), amisulpride (1 mgkg), or sulpiride (20 mgkg), also reversed the PCP-induced NOR deficit. Pimavanserin, a 5-HT(2A) inverse agonist, LY379268, and haloperidol did not potentiate the ability of subeffective SB269970 to improve the NOR deficit. Furthermore, the mGluR23 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-HT(7) 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.