Upregulation of CB1 receptors and agonist-stimulated [35S]GTPγS binding in the prefrontal cortex of depressed suicide victims

Endogenous and exogenous cannabinoids (CBs) acting through the CB1 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 CB1 receptors and mediated signaling in the dorsolateral prefrontal cortex (DLPFC) of subjects with major depression who had died by suicides (depressed suicides, DS). [H-3] CP-55,940 and CB1 receptor-stimulated [S-35] GTPgammaS binding sites were analyzed in membranes obtained from DLPFC of DS ( 10) and matched normal controls (10). Upregulation (24%, P<0.0001) of CB1 receptor density (B-max) was observed in DS (644.6 +/- 48.8 fmol/mg protein) compared with matched controls (493.3 +/- 52.7 fmol/mg protein). However, there was no significant alteration in the affinity of receptor (DS; 1.14 +/- 0.08 vs control; 1.12 +/- 0.10 nM). Higher density of CB1 receptors in DS (38%, P<0.001) was also demonstrated by Western blot analysis. The CB1 receptor-stimulated [S-35] GTPgammaS binding was significantly greater (45%, P<0.001) in the DLPFC of DS compared with matched controls. The observed upregulation of CB1 receptors with concomitant increase in the CB1 receptor-mediated [S-35] GTP gamma S binding suggests a role for enhanced cannabinoidergic signaling in the prefrontal cortex of DS. The cannabinoidergic system may be a novel therapeutic target in the treatment of depression and/or suicidal behavior.