Role of the sympathoadrenal axis in the cardiovascular response to cocaine in conscious unrestrained rats

We investigated the role of peripheral sympathetic neurons and the adrenal medulla in the cardiovascular responses to cocaine in conscious, unrestrained Sprague-Dawley rats. Surgical adrenal demedullation (ADM) and/or chemical peripheral sympathectomy was used to eliminate one or both components of the sympathoadrenal axis. Phentolamine (5 mg/kg i.v.) was used to evaluate whether cocaine elicited epinephrine (EPI) release from the adrenal medulla. Significant EPI release by cocaine would result in "epinephrine reversal" after phentolamine pretreatment. Cocaine (2.5 mg/kg i.v.) was used in all experiments except the dose-response relationship study. In normal rats, cocaine caused a transient increase in mean blood pressure (MBP). Pretreatment with phentolamine reversed this BP response and this depressor effect was blocked by propranolol (2 mg/kg i.v.) suggesting that the pressor effect of cocaine was mediated by EPI. Chemical sympathectomy alone partially inhibited the pressor effect of cocaine, but pretreatment with phentolamine still reversed the residual action of cocaine on MBP at this time. Two weeks after ADM, the effect of cocaine on MBP was not significantly different from that of the sham-operated rats. However, pretreatment with phentolamine inhibited but did not reverse the effect of cocaine on MBP at that time. In rats with both ADM and chemical sympathectomy, cocaine caused only a decrease in MBP that was not blocked by propranolol or atropine methylnitrate, presumably because of its direct depressive actions. Results of this study suggest that both peripheral sympathetic neurons and the adrenal medulla play important roles in the cardiovascular actions of cocaine.