Endocannabinoid system and stress and anxiety responses.

Cannabinoid agonists induce complex and often contradictory effects on anxiety in humans and experimental animals. The data from animal tests provide evidence of dose-dependent bidirectional modulation of anxiety by the cannabinoid system and the importance of environmental context. The mechanisms mediating the effects of cannabinoids on anxiety-related responses appear to involve CB1 and non-CB1 cannabinoid receptors. In addition, the CRH, GABA(A), cholecystokinin, opioid and serotonergic systems have also been implicated. Brain regions such as the amygdala, hippocampus and cortex, directly involved in the regulation of emotional behavior, contain high densities of CB1 receptors. Mutant mice lacking CB1 receptors show anxiogenic-like and depressive-like phenotypes in several tests, as well as profound alterations in their adrenocortical activity. Pharmacological blockade of CB1 receptors induces anxiety in rats, and inhibition of anandamide metabolism produces anxiolytic-like effects. Thus, the endocannabinoid system appears to play a pivotal role in the regulation of emotional states and may constitute a novel pharmacological target for anti-anxiety therapy.