Regulation of cannabinoid CB1 and CB2 receptors, neuroprotective mTOR and pro-apoptotic JNK1/2 kinases in postmortem prefrontal cortex of subjects with major depressive disorder.

Dysregulations of endocannabinoids and/or cannabinoid (CB) receptors have been implicated in the pathophysiology and treatment of major depressive disorder (MDD). CB1 and CB2 receptors, neuroprotective mTOR (mechanistic target of rapamycin) and pro-apoptotic JNK1/2 (c-Jun-N-terminal kinases) were quantified by immunoblotting in postmortem prefrontal cortex of MDD and controls, and further compared in antidepressant (AD)-free and AD-treated subjects. Neuroplastic proteins (PSD-95, Arc, spinophilin) were quantified in MDD brains. Total cortical CB1 glycosylated (≈54/64 kDa) receptor was increased in MDD (+20%, n=23, p=0.02) when compared with controls (100%, n=19). This CB1 receptor upregulation was quantified in AD-treated (+23%, n=14, p=0.02) but not in AD-free (+14%, n=9, p=0.34) MDD subjects. In the same MDD cortical samples, CB2 glycosylated (≈45 kDa) receptor was unaltered (all MDD: +11%, n=23, p=0.10; AD-free: +12%, n=9, p=0.31; AD-treated: +10%, n=14, p=0.23). In MDD, mTOR activity (p-Ser2448 TOR/t-TOR) was increased (all MDD: +29%, n=18, p=0.002; AD-free: +33%, n=8, p=0.03; AD-treated: +25%, n=10, p=0.04). In contrast, JNK1/2 activity (p-Thr183/Tyr185/t-JNK) was unaltered in MDD subjects. Cortical PSD-95, Arc, and spinophilin contents were unchanged in MDD. A relative limited sample size. Some MDD subjects had been treated with a variety of ADs. The results must be understood in the context of suicide victims with MDD. The upregulation of CB1 receptor density, but not that of CB2 receptor, as well as the increased mTOR activity in PFC/BA9 of subjects with MDD (AD-free/treated) support their contributions in the complex pathophysiology of MDD and in the molecular mechanisms of antidepressant drugs.