title: The role of 5-hydroxytryptamine 7 receptors in the phencyclidine-induced novel object recognition deficit in rats.
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-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-oxabicyclo[3.1.0]hexane-4,6-dicarboxylic acid (LY379268), a metabotropic glutamate receptor (mGluR) 2/3 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)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-HT(7) 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-HT(7) 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-HT(2A) 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-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.
authors.affiliation: Division of Psychopharmacology, Vanderbilt University Medical Center, Nashville, Tennessee, USA.
authors.forename: M
authors.initials: M
authors.lastname: Horiguchi
authors.forename: M
authors.initials: M
authors.lastname: Huang
authors.forename: H Y
authors.initials: HY
authors.lastname: Meltzer
mesh_terms: D000818:Animals; D003072:Cognition Disorders / Q000139:chemically induced* / Q000503:physiopathology / Q000517:prevention & control; D005106:Exploratory Behavior / Q000187:drug effects / Q000502:physiology*; D005260:Female; D010622:Phencyclidine / Q000633:toxicity*; D010636:Phenols / Q000494:pharmacology / Q000627:therapeutic use; D011897:Random Allocation; D051381:Rats; D020318:Rats, Long-Evans; D011985:Receptors, Serotonin / Q000502:physiology*; D021641:Recognition, Psychology / Q000187:drug effects / Q000502:physiology*; D012702:Serotonin Antagonists / Q000494:pharmacology / Q000627:therapeutic use; D013449:Sulfonamides / Q000494:pharmacology / Q000627:therapeutic use
chemical_list: D010636:Phenols; D011985:Receptors, Serotonin; C404922:SB 269970; D012702:Serotonin Antagonists; D013449:Sulfonamides; C104425:serotonin 7 receptor; D010622:Phencyclidine