Cannabinoid CB1 receptors mediate the anxiolytic effects induced by systemic alprazolam and intra-periaqueductal gray 5-HT1A receptor activation.

The endocannabinoid system has been implicated in the modulation of behaviors related to anxiety and panic disorders. Accordingly, facilitation of CB₁ receptor signaling reduces the consequences of aversive stimuli in animal models. However, the role of the CB₁ receptor in the effects of anxiolytic drugs has remained unclear. Here, we tested the hypothesis that the anxiolytic and panicolytic responses to systemic alprazolam injection and local 5-HT_1A receptor activation in the dorsolateral periaqueductal gray (dlPAG) depend on CB₁ receptor activation. Systemic injection of alprazolam (4 mg/kg) induced an anxiolytic-like effect in the elevated T maze (ETM) model of panic and anxiety, which was prevented by the CB₁ antagonist AM251 (0.3 mg/kg). Likewise, intra-dlPAG injection of the 5-HT_1A receptor agonist 8-OH-DPAT (3.2 nmol/0.2 u L) also reduced anxiety-like behavior, a response prevented by intra-dlPAG injection of AM251 (100 pmol/0.2 µL). 8-OH-DPAT (8 nmol/0.2 µL) also presented a panicolytic-like activity in the escape reaction induced by chemical stimulation of the dlPAG, which was not prevented by AM251 (100 pmol/0.2 µL). These results suggest that CB₁ receptor signaling is involved in the effects of anxiolytic drugs, with potential implications for developing new treatments for anxiety disorders.