title: Detrimental effect of clomipramine on hippocampus-dependent learning in an animal model of obsessive-compulsive disorder induced by sensitization with d2/d3 agonist quinpirole.
abstract: Quinpirole (QNP) sensitization is one of the commonly used animal models of obsessive-compulsive disorder (OCD). We have previously shown that QNP-sensitized animals display a robust cognitive flexibility deficit in an active place avoidance task with reversal in Carousel maze. This is in line with numerous human studies showing deficits in cognitive flexibility in OCD patients. Here we explored the effect of clomipramine, an effective OCD drug that attenuates compulsive checking in QNP, on sensitized rats in acquisition and reversal performances in an active place avoidance task. We found that the addition of clomipramine to QNP-sensitization impairs acquisition learning to a degree that reversal learning could not be tested. In a hippocampal-independent two-way active avoidance task clomipramine did not have an effect on acquisition learning in QNP-treated rats; suggesting that the detrimental effect of clomipramine is hippocampus based. We also tested the effect of risperidone in QNP-sensitized animals, which is not effective in OCD treatment. Risperidone also marginally impaired acquisition learning of QNP-sensitized animals, but not reversal. Moreover, we explored the effect of the augmentation of clomipramine treatment with risperidone in QNP-sensitized rats- a common step in treating SRI-unresponsive OCD patients. Only under this treatment regime animals were unimpaired in both acquisition and reversal learning. Augmentation of SRI with neuroleptics therefore could be beneficial for improving cognitive flexibility, and possibly be considered a first line of treatment in patients with reduced cognitive flexibility.
authors.affiliation: Institute of Physiology, Academy of Sciences of the Czech Republic, Videnska 1083, 142 20, Prague, Czech Republic. Electronic address: hana.hatalova@fgu.cas.cz.
authors.forename: Hana
authors.initials: H
authors.lastname: Hatalova
authors.affiliation: Institute of Physiology, Academy of Sciences of the Czech Republic, Videnska 1083, 142 20, Prague, Czech Republic.
authors.forename: Dominika
authors.initials: D
authors.lastname: Radostova
authors.affiliation: Institute of Physiology, Academy of Sciences of the Czech Republic, Videnska 1083, 142 20, Prague, Czech Republic.
authors.forename: Adela
authors.initials: A
authors.lastname: Pistikova
authors.affiliation: Institute of Physiology, Academy of Sciences of the Czech Republic, Videnska 1083, 142 20, Prague, Czech Republic; National Institute of Mental Health, Topolova 748, 250 67, Klecany, Czech Republic.
authors.forename: Karel
authors.initials: K
authors.lastname: Vales
authors.affiliation: Institute of Physiology, Academy of Sciences of the Czech Republic, Videnska 1083, 142 20, Prague, Czech Republic. Electronic address: ales.stuchlik@fgu.cas.cz.
authors.forename: Ales
authors.initials: A
authors.lastname: Stuchlik
mesh_terms: D000704:Analysis of Variance; D000818:Animals; D001362:Avoidance Learning / Q000187:drug effects; D002997:Clomipramine / Q000627:therapeutic use*; D004195:Disease Models, Animal; D018491:Dopamine Agonists / Q000633:toxicity*; D004597:Electroshock; D004924:Escape Reaction / Q000187:drug effects; D006624:Hippocampus / Q000187:drug effects* / Q000502:physiology; D008124:Locomotion / Q000187:drug effects; D008297:Male; D018782:Maze Learning / Q000187:drug effects; D009771:Obsessive-Compulsive Disorder / Q000139:chemically induced* / Q000188:drug therapy*; D019257:Quinpirole / Q000633:toxicity*; D051381:Rats; D020318:Rats, Long-Evans; D018967:Risperidone / Q000494:pharmacology; D012702:Serotonin Antagonists / Q000494:pharmacology; D017367:Selective Serotonin Reuptake Inhibitors / Q000627:therapeutic use*
chemical_list: D002997:Clomipramine; D018491:Dopamine Agonists; D019257:Quinpirole; D018967:Risperidone; D012702:Serotonin Antagonists; D017367:Selective Serotonin Reuptake Inhibitors
keywords: Animal model; Antidepressant; Antipsychotics; Obsessive-compulsive disorder; Quinpirole; Rat