Cocaine is a major cause of life-threatening cardiovascular emergencies (hypertensive crisis, myocardial infarcts. While these emergencies are related to excessive adrenergic stimulation of the cardiovascular system, our understanding of the underlying mechanisms is far from complete and current therapies are unsatisfactory. The prevailing view is that cocaine blocks norepinephrine (NE) reuptake in peripheral sympathetic terminals, thereby increasing (NE). During the past two grant cycles, our studies in cocainena'ive human subjects have challenged the predominance of this mechanism and demonstrated instead that cocaine stimulates the human cardiovascular system primarily by acting in the brain to increase sympathetic nerve activity (SNA), the neural stimulus to NE release. We now hypothesize that the central sympatholytic action of alpha 2 adrenergic receptor (AR) agonists can be utilized to counter the centrally-driven cardiovascular consequences of cocaine. These agonists could mitigate effects of cocaine by acting on brainstem alpha 2 ARs to decrease SNA as well as on presynaptic alpha 2ARs on sympathetic nerve terminals to inhibit NE release. But they also activate post-junctional alpha 2 ARs on vascular smooth muscle which, might exacerbate cocaineinduced vasoconstriction. Utilizing rigorously-defined cardiovascular phenotypes in a controlled laboratory setting, we will test whether the efficacy of potent alpha 2AR agonist (i.v. dexmedetomidine) to reverse the sympathomimetic actions of cocaine is maintained even under conditions in which either (a) the sympatholytic effects of alpha 2 ARs might be attenuated (black ethnicity, loss-of- function mutation in alpha 2C AR, chronic cocaine exposure) or (b) postjunctional alpha 2AR mediated vasoconstriction might be augmented (coronary disease, gain-of-function mutations in the alpha 2B AR or post-receptor signaling). The distinctive features of this proposal include the: (1) use of state-of-the-art techniques in integrative physiology; (2) focus on activation of SNA by cocaine, which traditionally has been viewed as a peripherally-acting sympathomimetic; (3) pharmacogenetics, and (4) study of chronic cocaine abusers. This translational research should fill in some important gaps in our mechanistic understanding of the sympathomimetic actions of cocaine on the human cardiovascular system and hopefully begin to inform therapy. [unreadable] [unreadable]