title: Chronic blockade of CB(1)  receptors reverses startle gating deficits and associated neurochemical alterations in rats reared in isolation.
abstract: OBJECTIVE
  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 CB(1) 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.
  
  
  METHODS
  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 was explored in specific brain regions following isolation rearing. The effect of chronic AM251 administration on PPI response and the associated biochemical alterations was assessed.
  
  
  RESULTS
  The disrupted PPI response in isolation-reared rats was paralleled by significant alterations in 2-AG content and dopamine and glutamate receptor densities in specific brain regions. Chronic AM251 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 partially antagonized isolation-induced changes in dopamine and glutamate receptors.
  
  
  CONCLUSIONS
  These results demonstrate the efficacy of chronic AM251 treatment in the recovery of isolation-induced disruption of PPI. Moreover, AM251 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 support the potential antipsychotic-like activity of CB(1) receptor blockade.
  
  
  BACKGROUND
  This article is part of a themed section on Cannabinoids. To view the other articles in this section visit http://dx.doi.org/10.1111/bph.2012.167.issue-8.
authors: Department of Theoretical and Applied Sciences, Biomedical Division and Center of Neuroscience, University of Insubria, Busto Arsizio (VA), Italy.
authors: E
authors: E
authors: Zamberletti
authors: F
authors: F
authors: Piscitelli
authors: F
authors: F
authors: Cadeddu
authors: T
authors: T
authors: Rubino
authors: W
authors: W
authors: Fratta
authors: P
authors: P
authors: Fadda
authors: V
authors: V
authors: Di Marzo
authors: D
authors: D
authors: Parolaro
mesh_terms: D000161:Acoustic Stimulation; D000818:Animals; D001522:Behavior, Animal / Q000187:drug effects; D001921:Brain / Q000187:drug effects* / Q000502:physiology; D063387:Cannabinoid Receptor Antagonists / Q000494:pharmacology*; D063388:Endocannabinoids / Q000502:physiology; D008297:Male; D010880:Piperidines / Q000494:pharmacology*; D011720:Pyrazoles / Q000494:pharmacology*; D051381:Rats; D043884:Receptor, Cannabinoid, CB1 / Q000037:antagonists & inhibitors* / Q000502:physiology; D055139:Sensory Gating / Q000187:drug effects*; D012934:Social Isolation
chemical_list: D063387:Cannabinoid Receptor Antagonists; D063388:Endocannabinoids; D010880:Piperidines; D011720:Pyrazoles; D043884:Receptor, Cannabinoid, CB1; C103505:AM 251