Hungund B L, Vinod K Y, Kassir S A, Basavarajappa B S, Yalamanchili R, Cooper T B, Mann J J, Arango V
New York State Psychiatric Institute, New York, NY 10962, USA.
Mol Psychiatry. 2004 Feb;9(2):184-90. doi: 10.1038/sj.mp.4001376.
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). [(3)H]CP-55,940 and CB(1) receptor-stimulated [(35)S]GTPgammaS binding sites were analyzed in membranes obtained from DLPFC of DS (10) and matched normal controls (10). Upregulation (24%, P<0.0001) of CB(1) 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 CB(1) receptors in DS (38%, P<0.001) was also demonstrated by Western blot analysis. The CB(1) receptor-stimulated [(35)S]GTPgammaS binding was significantly greater (45%, P<0.001) in the DLPFC of DS compared with matched controls. The observed upregulation of CB(1) receptors with concomitant increase in the CB(1) receptor-mediated [(35)S]GTPgammaS 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.
内源性和外源性大麻素（CBs）通过CB(1)受体发挥作用，与多种行为和神经内分泌功能的调节有关。乙醇对小鼠大脑内源性大麻素系统的调节，以及自杀和情绪障碍与酒精中毒的关联，提示大麻素系统可能参与了抑郁症和自杀的病理生理过程。因此，本研究旨在检测自杀身亡的重度抑郁症患者（抑郁自杀者，DS）背外侧前额叶皮质（DLPFC）中CB(1)受体的水平及其介导的信号传导。对DS组（10例）和匹配的正常对照组（10例）DLPFC提取的膜进行[(3)H]CP-55,940和CB(1)受体刺激的[(35)S]GTPγS结合位点分析。与匹配的对照组（493.3±52.7 fmol/mg蛋白）相比，DS组（644.6±48.8 fmol/mg蛋白）的CB(1)受体密度（B(max)）上调（24%，P<0.0001）。然而，受体亲和力无显著改变（DS组；1.14±0.08 vs对照组；1.12±0.10 nM）。蛋白质印迹分析也显示DS组CB(1)受体密度更高（38%，P<0.001）。与匹配的对照组相比，DS组DLPFC中CB(1)受体刺激的[(35)S]GTPγS结合显著增加（45%，P<0.001）。观察到的CB(1)受体上调以及CB(1)受体介导的[(35)S]GTPγS结合增加，提示增强的大麻素信号传导在DS组前额叶皮质中发挥作用。大麻素系统可能是治疗抑郁症和/或自杀行为的新治疗靶点。
