Facilitation of endocannabinoid effects in the ventral hippocampus modulates anxiety-like behaviors depending on previous stress experience.

Although several pieces of evidence indicate that the endocannabinoid system modulates anxiety-like behaviors and stress adaptation, few studies have investigated the brain sites of these effects. The ventral hippocampus (VHC) has been related to anxiety behaviors and has a high expression of cannabinoid-1 (CB1) receptors. Moreover, endocannabinoid signaling in the hippocampus is proposed to regulate stress adaptation. In the present study we investigated the role of previous stressful experience on the effects of AM404, an anandamide uptake inhibitor, microinjected into the VHC of rats submitted to the elevated plus maze (EPM), a widely used animal model of anxiety. Stressed animals were forced restrained for two h 24 h before the test. AM404 (5-50 pmol) microinjection promoted an anxiogenic-like effect in non-stressed rats but decreased anxiety in stressed animals. AM251 (0.01 to 1000 pmol), a CB1 receptor antagonist, failed to change behavior in the EPM over a wide dose range but prevented the effects of AM404. Anxiolytic-like effects of AM404 (5 pmol) intra-VHC injection were also observed in the Vogel conflict test (VCT), another model of anxiety that involves previous exposure to stressful situations (48 h of water deprivation). These results suggest that facilitation of endocannabinoid system neurotransmission in the ventral hippocampus modulates anxiety-like behaviors and that this effect depends on previous stress experience.