The International Journal of Neuropsychopharmacology

Table of Contents - 2011 - Volume 14, Issue 01 (Thematic Section: New Developments in Schizophrenia Research)  

Thematic Section: New Developments in Schizophrenia Research

Cannabinoid CB1 receptor antagonism prevents neurochemical and behavioural deficits induced by chronic phencyclidine

Cinzia Guidalia1*, Daniela Viganòa1a2*, Stefania Petrosinoa3, Erica Zamberlettia1, Natalia Realinia1, Giorgio Binellia4, Tiziana Rubinoa1, Vincenzo Di Marzoa3 and Daniela Parolaroa1a2 c1

a1 DBSF and Neuroscience Center, University of Insubria, Varese, Italy

a2 Zardi-Gori Foundation, Milan, Italy

a3 Endocannabinoid Research Group, Institute of Biomolecular Chemistry, CNR, Naples, Italy

a4 DBSM, University of Insubria, Varese, Italy

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.

(Received September 15 2009)

(Reviewed October 16 2009)

(Revised January 26 2010)

(Accepted January 29 2010)

(Online publication March 03 2010)

Key Words:

Correspondence:

c1 Address for correspondence: Professor D. Parolaro, DBSF and Neuroscience Center, University of Insubria, Via A. da Giussano 10, 21052 Busto Arsizio, Varese, Italy. Tel.: 0039 0331 339417 Fax: 0039 0331 339459 Email: daniela.parolaro@uninsubria.it

Footnotes

* These authors contributed equally to this work.

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