The Endocannabinoid System In Depression

Background Endocannabinoid system include cannabinoid receptors, endocannabinoids and the enzymes that involve in the synthesise and the hydrolyse the endocannabinoids.There are two main endocannabinoids that have been identified clearly, arachidonoylethanolamine (anandemide or AEA) and 2-AG, they are similar in molecular structure with terahydrocannabinol(THC), the natural component of Marijuanan.There are currently two known subtypes, termed CB1and CB2. The CB1 receptor is expressed mainly in the brain (central nervous system, CNS), but also in the lungs, liver and kidneys. The CB2 receptor is mainly expressed in the immune system and in hematopoietic cells. The protein sequences of CB1and CB2 receptors are about 44% similar. When only the transmembrane regions of the receptors are considered, amino acid similarity between the two receptor subtypes is approximately 68%.The nucleus accumbens (NAc) is a critical component of the reward circuitry and dysfunction of the NAc may account for anhedonia and other symptoms of depression. The NAc is an important anatomical substrate for motivation and reward and dysfunction of the NAc could account for anhedonia, decreased sex drive, social withdrawal, and other symptoms of depression. The present study has identified that alterations of eCB signaling might occur in the NAc in depression.Objective To investigated whether alterations in endocannabinoid (eCB) signaling in the NAc contribute to depression-like behaviors induced by chronic unpredictable stress (CUS) in mice. Method1. Male C57BL/6J mice (8-10 weeks of age) were subjected to chronic mild unpredictable stress (CUS) for a totle of 8-10 week to establish the depression model.2. After the CUS procedure, mice were subject to a batter of behavior test to evaluate the state of depression. The behavior test include sucrose-intake test open field test (OPT), novelty suppressed feeding (NSF) and forced swimming test.3. Control and CUS-exposed mice were anesthetized by isoflurane inhalation and decapitated and the brains were removed immediately and frozen by dry ice, the striatum were disseccted. Trunk blood was collected, and adrenals and thymus were excised and weighed immediately. Serum corticosterone concentrations were determined by enzyme-linked immunosorbent assay kit. Brain AEA and 2-AG tissue contents were determined using isotope-dilution liquid chromatography electrospray ionization tandem mass spectrometry.4. Striatal slices containing the NAc (250?m thick) were prepared and three types of eCB/CB1 receptor-mediated synaptic plasticity were compared, including depolarization-induced suppression of excitation (DSE), long-term depression (LTD), and the depression of field excitatory postsynaptic potentials (fEPSPs) induced by group I metabotropic glutamate receptor agonist DHPG and the effect of CB1 receptor agonist WIN 55,212-2.Result CUS (5-6 week exposure to stressors), but not sub-CUS (1 week exposure to stressors), induces depression-like behaviors and impairs these forms of eCB/CB1 receptor-mediated plasticity examined in the NAc core. Neither sub-CUS nor CUS altered the tissue contents of the eCBs anandamide and 2-arachidonoylglycerol in the striatum. However, exposure to CUS, but not sub-CUS, attenuated the depression of fEPSPs induced by the CB1 receptor agonist WIN 55,212-2. CUS exposure reduced the maximal effect without affecting the EC50 of WIN 55,212-2 to induce fEPSP depression. Thus, impaired CB1 receptor function could account for CUS-induced deficiency in eCB signaling in the NAc. Both CUS-induced deficiency in eCB signaling and depression-like behaviors were reversed by in vivo administration of antidepressant fluoxetine.Conclusion These results suggest that down-regulation of the eCB signaling in the NAc occurs following CUS and contributes to the pathophysiology of depression. Marijuana (cannabis) and its active constituent?9-tetrahydrocannabinol (THC) elevate mood and ease anxiety in humans and CB1 receptor agonists exert antidepressant-like behavioral effects in animals. Modulation of the endocannabinoid (eCB) system may represent a useful strategy for the treatment of depression. Inhibitors of eCB degradation amplify endogenous cannabinoid activity in a temporal- and spatial-specific manner and could be superior to direct-acting CB1 agonists as therapeutic agents. The eCB ligand 2-arachidonoylglycerol (2-AG) is inactivated by monoacylglycerol lipase (MAGL). However, whether MAGL inhibition produces antidepressant-like behavioral effects remains unknown. JZL184 is a recently developed selective MAGL inhibitor that increases 2-AG levels in the brain. We report that chronic in vivo administration of JZL184 produced antidepressant-like behavioral effects in a chronic unpredictable stress (CUS) model of depression in mice, and these effects were blocked by the CB1 antagonist rimonabant. Chronic JZL184 reversed CUS-induced decreases in the number of bromodeoxyuridine (BrdU)-labeled neural progenitor cells and doublecortin-positive immature neurons in the in the dentate gyrus of the hippocampus and facilitated a form of long-term potentiation (LTP) that is dependent on hippocampal neurogenesis. These results suggest that MAGL inhibition produces antidepressant-like effects by prompting hippocampal neurogenesis and that MAGL is a potential target for pharmacotherapy of depression.