title: Cannabinoid CB1 receptor antagonism prevents neurochemical and behavioural deficits induced by chronic phencyclidine.
abstract: Clinical and laboratory studies suggest that the endocannabinoid system is involved in schizophrenia disorders. Recent evidence indicates that cannabinoid receptor (CB1) antagonists have a pharmacological profile similar to antipsychotic drugs. We investigated the behavioural and biochemical effects of the CB1 antagonist AM251 in a phencyclidine (PCP) animal paradigm modelling the cognitive deficit and some negative symptoms of schizophrenia. Chronic AM251 (0.5 mg/kg for 3 wk) improved the PCP-altered recognition memory, as indicated by a significant amelioration of the discrimination index compared to chronic PCP alone (2.58 mg/kg for 1 month). AM251 also reversed the PCP-induced increase in immobility in the forced swim test resembling avolition, a negative sign of schizophrenia. In order to analyse the mechanisms underlying these behaviours, we studied the effects of AM251 on the endocannabinoid system (in terms of CB1 receptor density and functional activity and endocannabinoid levels) and c-Fos protein expression. The antagonist counteracted the alterations in CB1 receptor function induced by PCP in selected cerebral regions involved in schizophrenia. In addition, in the prefrontal cortex, the key region in the integration of cognitive and negative functions, AM251 markedly raised anandamide levels and reversed the PCP-induced increase of 2-arachidonoylglycerol concentrations. Finally, chronic AM251 fully reversed the PCP-elicited expression of c-Fos protein in the prefrontal cortical region. These findings suggest an antipsychotic-like profile of the CB1 cannabinoid receptor antagonist which, by restoring the function of the endocannabinoid system, might directly or indirectly normalize some of the neurochemical maladaptations present in this schizophrenia-like animal model.
authors.affiliation: DBSF and Neuroscience Center, University of Insubria, Varese, Italy.
authors.forename: Cinzia
authors.initials: C
authors.lastname: Guidali
authors.forename: Daniela
authors.initials: D
authors.lastname: Viganò
authors.forename: Stefania
authors.initials: S
authors.lastname: Petrosino
authors.forename: Erica
authors.initials: E
authors.lastname: Zamberletti
authors.forename: Natalia
authors.initials: N
authors.lastname: Realini
authors.forename: Giorgio
authors.initials: G
authors.lastname: Binelli
authors.forename: Tiziana
authors.initials: T
authors.lastname: Rubino
authors.forename: Vincenzo
authors.initials: V
authors.lastname: Di Marzo
authors.forename: Daniela
authors.initials: D
authors.lastname: Parolaro
mesh_terms: D000818:Animals; D001522:Behavior, Animal / Q000187:drug effects*; D063385:Cannabinoid Receptor Modulators / Q000378:metabolism; D004195:Disease Models, Animal; D018691:Excitatory Amino Acid Antagonists / Q000378:metabolism / Q000494:pharmacology* / Q000633:toxicity; D006624:Hippocampus / Q000187:drug effects / Q000503:physiopathology; D008297:Male; D009043:Motor Activity / Q000187:drug effects; D010622:Phencyclidine / Q000633:toxicity*; D010880:Piperidines / Q000494:pharmacology*; D017397:Prefrontal Cortex / Q000187:drug effects / Q000503:physiopathology; D011720:Pyrazoles / Q000494:pharmacology*; D051381:Rats; D043884:Receptor, Cannabinoid, CB1 / Q000037:antagonists & inhibitors*; D012559:Schizophrenia / Q000139:chemically induced / Q000188:drug therapy* / Q000503:physiopathology; D013997:Time Factors
chemical_list: D063385:Cannabinoid Receptor Modulators; D018691:Excitatory Amino Acid Antagonists; D010880:Piperidines; D011720:Pyrazoles; D043884:Receptor, Cannabinoid, CB1; C103505:AM 251; D010622:Phencyclidine