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

Abstract

Background: Dysregulations of endocannabinoids and/or cannabinoid (CB) receptors have been implicated in the pathophysiology and treatment of major depressive disorder (MDD).

Methods: 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.

Results: 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.

Limitations: 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.

Conclusions: 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.

Keywords: Antidepressant drugs; Cannabinoid CB(1) and CB(2) receptors; Major depressive disorder; Mechanistic target of rapamycin (mTOR); Postmortem human brain (dorsolateral PFC); c-Jun-N-terminal kinase (JNK1/2).