Cerebral Cortex Advance Access originally published online on October 5, 2007
Cerebral Cortex 2008 18(6):1292-1301; doi:10.1093/cercor/bhm161
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Role in Anxiety Behavior of the Endocannabinoid System in the Prefrontal Cortex
1 DBSF, Pharmacology Section and Center of Neuroscience, University of Insubria, via A. da Giussano 10, 21052 Busto Arsizio (VA), Italy, 2 Endocannabinoid Research Group, Institute of Biomolecular Chemistry, Consiglio Nazionale delle Ricerche, via Campi Flegrei 34, 80078 Pozzuoli (Napoli), Italy, 3 Department of Biomedical Sciences, University of Teramo, 64100 Teramo and European Center for Brain Research (CERC)/IRCCS S. Lucia Foundation, 00143 Rome, Italy
Address correspondence to D. Parolaro, Pharmacology Section and Center of Neuroscience, University of Insubria, via A. da Giussano 10, 21052 Busto Arsizio (VA), Italy. Email: daniela.parolaro{at}uninsubria.it.
In the present study we explored with a multidisciplinary approach, the role of anandamide (AEA) in the modulation of anxiety behavior at the level of the prefrontal cortex (PFC). Low doses of the metabolically stable AEA analog, methanandamide, microinjected into the PFC, produced an anxiolytic-like response in rats, whereas higher doses induced anxiety-like behaviors. Pretreatment with the selective antagonist of CB1 or TRPV1 receptors (AM251 and capsazepine, respectively) suggested that the anxiolytic effect evoked by AEA might be due to the interaction with the CB1 cannabinoid receptor, whereas vanilloid receptors seem to be involved in AEA anxiogenic action. When AEA contents in the PFC were increased by microinjecting the selective inhibitor of fatty acid amide hydrolase (FAAH), URB597, we observed an anxiolytic response only at low doses of the compound and no effect or even an anxiogenic profile at higher doses. In line with this, a marked decrease of AEA levels in the PFC, achieved by lentivirus-mediated local overexpression of FAAH, produced an anxiogenic response. These findings support an anxiolytic role for physiological increases in AEA in the PFC, whereas more marked increases or decreases of this endocannabinoid might lead to an anxiogenic response due to TRPV1 stimulation or the lack of CB1 activation, respectively.
Key Words: anandamide • anxiety • CB1 receptors • FAAH • prefrontal cortex • TRPV1 receptors
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