Chronic Blockade of CB1 Receptors Reverses Startle Gating Deficits and Associated Neurochemical Alterations in Isolation Reared Rats.

Background and purpose:  Pharmacological interventions aimed at restoring the endocannabinoid system functionality have been proposed as potential tools in the treatment of schizophrenia. Based on our previous results suggesting a potential antipsychotic-like profile of the CB1 receptor inverse agonist/antagonist, AM251, here we further investigated the effect of chronic AM251 administration on the alteration of the sensorimotor gating functions and endocannabinoid levels induced by isolation rearing in rats. Experimental approach:  Using the post-weaning social isolation rearing model, we studied its influence on sensorimotor gating functions, through the PPI paradigm. The presence of alterations in the endocannabinoid levels as well as in dopamine and glutamate receptor densities were explored in specific brain region following isolation rearing. The effect of chronic AM251 administration on PPI response and the associated biochemical alterations was assessed. Key results:  Disrupted PPI response in isolation reared rats was paralleled by significant alterations in 2-AG content as well as dopamine and glutamate receptor densities in specific brain regions. Chronic AM251 treatment completely restored normal PPI response in isolated rats. This behavioural recovery was paralleled by the normalization of 2-AG levels in all the brain areas analysed. Furthermore, AM251 administration partially antagonized isolation-induced changes in dopamine and glutamate receptors. Conclusions and Implications:  These results demonstrate the efficacy of chronic AM251 treatment in the recovery of isolation-induced disruption of PPI. Moreover, AM251 treatment counteracted the imbalances in the endocannabinoid content, specifically 2-AG levels, and partially reversed the alterations in dopamine and glutamate systems associated with the disrupted behaviour. Together, these findings strengthen the potential antipsychotic-like activity of CB1 receptor blockade