Detrimental effect of clomipramine on hippocampus-dependent learning in an animal model of obsessive-compulsive disorder induced by sensitization with d2/d3 agonist quinpirole

• Published in: Behavioural brain research 2017-01, Vol.317, p.210-217
• Main Authors: Hatalova, Hana, Radostova, Dominika, Pistikova, Adela, Vales, Karel, Stuchlik, Ales
• Format: Article
• Language: English
• Subjects: Analysis of Variance; Animal model; Animals; Antidepressant; Antipsychotics; Avoidance Learning - drug effects; Clomipramine - therapeutic use; Disease Models, Animal; Dopamine Agonists - toxicity; Electroshock; Escape Reaction - drug effects; Hippocampus - drug effects; Hippocampus - physiology; Locomotion - drug effects; Male; Maze Learning - drug effects; Obsessive-compulsive disorder; Obsessive-Compulsive Disorder - chemically induced; Obsessive-Compulsive Disorder - drug therapy; Quinpirole; Quinpirole - toxicity; Rat; Rats; Rats, Long-Evans; Risperidone - pharmacology; Serotonin Antagonists - pharmacology; Serotonin Uptake Inhibitors - therapeutic use
• ISSN: 0166-4328; 1872-7549
• DOI: 10.1016/j.bbr.2016.09.042

•Active place avoidance with reversal is a test of cognitive flexibility.•Quinpirole-sensitized rats in an animal model of OCD display a flexibility deficit.•Clomipramine added to quinpirole causes a severe learning deficit.•Risperidone added to clomipramine and quinpirole rescues performance. 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.