Elevated levels of endocannabinoids and CB1 receptor-mediated G-protein signaling in the prefrontal cortex of alcoholic suicide

Background: Alcoholism is often comorbid with mood disorders and suicide. We recently reported an upregulation of CB1 receptor-mediated signaling in the dorsolateral prefrontal cortex (DLPFC) of subjects with major depression who died by suicide. In the present study, we sought to determine whether the endocannabinoid (EC) system plays a role in suicide in alcoholism. Methods: The density of CB1 receptor and its mediated [S-35]GTPgammaS signaling were measured in the DLPFC of alcoholic suicides (AS) (n = 11) and chronic alcoholics (CA) (n = 11). The levels of ECs were measured by a liquid chromatograph/mass spectrometry. Results: The CB1 receptor density was higher in AS compared with the CA group in the DLPFC. Western blot analysis confirmed a greater immunoreactivity of the CB1 receptor in AS. The CB1 receptor-mediated [S-35]GTPgammaS binding indicated a greater signaling in AS. Higher levels of N-arachidonyl ethanolamide and 2-arachidonylglycerol were observed in the DLPFC and AS. Conclusion: The elevated levels of ECs, CB1 receptors, and CB1 receptor-mediated [S-35]GTPgammaS binding strongly suggest a hyperactivity of endocannabinoidergic signaling in AS. EC system may be a novel therapeutic target for the treatment of suicidal behavior.