Endocannabinoid 2-AG reduces fear and anxiety in rats through CB1 and CB2 receptors in a key brain defense region

2-AG injected into the dorsolateral PAG reduced contextual fear expression and produced anxiolytic effects in the Vogel conflict test, both dependent on CB1 and CB2 receptor activation. However, the Vogel test required higher doses, and monoacylglycerol lipase inhibitors (which block 2-AG breakdown) were effective only in the fear conditioning test.

Male Wistar rats received injections of 2-AG or its hydrolysis inhibitors into the dorsolateral periaqueductal gray, then were tested in contextual fear conditioning and Vogel conflict tests. CB1 and CB2 receptor antagonists were used to determine receptor involvement.

2-AG is the most abundant endocannabinoid in the brain, and understanding its anti-anxiety effects in specific brain regions could inform development of targeted anxiolytic drugs that avoid the psychoactive effects of THC.

While anandamide (the other major endocannabinoid) loses its anxiolytic effect at higher concentrations, 2-AG may offer a more reliable therapeutic window, making it an attractive target for anxiety treatment development.

Only male rats tested. Direct brain injection does not reflect realistic drug delivery. Effects varied by anxiety model, suggesting context-dependent action. No behavioral measures of side effects assessed.