Brain stem endocannabinoid system underpins cocaine-induced cardiovascular dysregulation

抄録

Cocaine is famous as a crucial culprit in addiction and relevant crime. However cardiovascular failure is commonly manifested by cocaine abusers but the underlying mechanism within brain stem is least investigated. Since the rostral ventrolateral medulla (RVLM) is known classically in blood pressure maintenance, we investigated whether brain stem cardiovascular dysregulation elicited by endocannabinoid system underpins cocaine-induced circulatory failure. Microinjection of cocaine into RVLM of Sprague-Dawley rats produced a decrease of blood pressure, heart rate and baroreflex-mediated vasomotor tone. Cocaine also increased the endogenous endocannabinoids (2-arachidonoylglycerol and anandamide), downregulated their respective degradative enzymes (monoacylglycerol lipase and N-acyl phosphatidylethanolamine phospholipase D) and activated of cannabinoid receptor 1 (CB1R) and transient receptor potential vanilloid receptor 1 (TRPV1), alongside with an upregulation of cleaved caspase-3 and DNA fragmentation in the RVLM. The aforementioned cocaine-elicited detrimental responses was mimicked by direct administration of endogenous endocannabinoids into RVLM, blunted by specific blockade of CB1R or TRPV1 and antagonized by specific activation of CB2R in the RVLM. We conclude that CB1R- and TRPV1-depedent activation, rather than CB2R activation, of endocannabinoid system leading to apoptosis in RVLM is responsible for brain stem cardiovascular dysregulation and circulatory failure associated with cocaine intoxication.