Endogenous and exogenous cannabinoids (CBs) acting through the CB 1 receptors have been implicated in the regulation of several behavioral and neuroendocrine functions. Modulation of endocannabinoidergic system by ethanol in mouse brain, and the association of suicide and mood disorders with alcoholism suggest possible involvement of the cannabinoidergic system in the pathophysiology of depression and suicide. Therefore, the present study was undertaken to examine the levels of CB 1 receptors and mediated signaling in the dorsolateral prefrontal cortex (DLPFC) of subjects with major depression who had died by suicides (depressed suicides, DS).

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Recent studies have indicated a role for the endocannabinoid system in ethanol-related behaviors. This study examined the effect of pharmacological activation, blockade, and genetic deletion of the CB 1 receptors on ethanol-drinking behavior in ethanol preferring C57BL/6J (B6) and ethanol nonpreferring DBA/2J (D2) mice. The deletion of CB 1 receptor significantly reduced the ethanol preference. Although the stimulation of the CB 1 receptor by CP-55,940 markedly increased the ethanol preference, this effect was found to be greater in B6 than in D2 mice. The antagonism of CB 1 receptor function by SR141716A led to a significant reduction in voluntary ethanol preference in B6 than D2 mice. A significant lower hypothermic and greater sedative response to acute ethanol administration was observed in both the strains of CB 1 -/-mice than wild-type mice. Interestingly, genetic deletion and pharmacological blockade of the CB 1 receptor produced a marked reduction in severity of handling-induced convulsion in both the strains. The radioligand binding studies revealed significantly higher levels of CB 1 receptor-stimulated G-protein activation in the striatum of B6 compared to D2 mice. Innate differences in the CB 1 receptor function might be one of the contributing factors for higher ethanol drinking behavior. The antagonists of the CB 1 receptor may have therapeutic potential in the treatment of ethanol dependence.

The aim of this study was to examine the role of fatty acid amide hydrolase (FAAH) on ethanol sensitivity, preference, and dependence. The deletion of FAAH gene or the inhibition of FAAH by carbamoyl‐biphenyl‐3‐yl‐cyclohexylcarbamate (URB597) (0.1 mg/kg) markedly increased the preference for ethanol. The study further reveals that URB597 specifically acts through FAAH and that cannabinoid‐1 (CB1) receptor is critical for N‐arachidonoyl ethanolamide (AEA) mediated ethanol‐reinforced behavior as revealed by lack of URB597 effect in both FAAH and CB1−/− mice compared with vehicle‐treated −/− mice. The FAAH −/− mice displayed a lower sensitivity to hypothermic and sedative effects to acute ethanol challenge. The FAAH −/− mice also exhibited a reduction in the severity of handling‐induced convulsions following withdrawal from chronic ethanol exposure. The CB1 receptor and proenkephalin gene expressions, and CB1 receptor and μ‐opioid (MO) receptor‐mediated G‐protein activation were found to be significantly lower in the caudate‐putamen, nucleus accumbens core and shell of FAAH −/− than +/+ mice. Interestingly, the MO receptor‐stimulated G‐protein signaling was greater in the striatum of FAAH −/− than +/+ mice following voluntary ethanol consumption. These findings suggest that an elevation in the AEA content and its action on the limbic CB1 receptor and MO receptor might contribute to ethanol‐reinforced behavior. Treatment with drugs that decrease AEA tone might prove useful in reducing excessive ethanol consumption.