Cocaine abuse has reached epidemic proportions in the United States and has emerged as a major cause of life-threatening cardiovascular emergencies. While these emergencies clearly are related to excessive adrenergic stimulation of the cardiovascular system, our understanding of the underlying mechanisms mediating cocaine's sympathomimetic effects is far from complete. The prevailing view is that cocaine blocks the norepinephrine reuptake transporter in peripheral sympathetic nerve terminals, thereby increasing norepinephrine concentrations in the synaptic cleft. However, our work in the past grant cycle challenges the predominance of this mechanism and demonstrates that in cocaine-naive healthy humans: (1) Intranasal cocaine stimulates postganglionic sympathetic nerve activity (SNA), the neural stimulus to norepinephrine release; and (2) Sinoaortic baroreflexes play a pivotal role in buffering this cocaine-induced sympathetic excitation. The interplay between these excitatory and inhibitory neural influences seems to determine the net effect of cocaine on SNA targeted to the human peripheral circulation. We now turn our attention to cocaine abuse. Because the vast majority of cocaine abusers also abuse tobacco, particular attention will be paid to key interactions between the sympathomimetic effects of cocaine and nicotine. Our major new hypothesis is that cocaine greatly amplifies an otherwise subtle sympathomimetic action of nicotine by two separate mechanisms: (1) When administered concomitantly, cocaine and nicotine interact acutely to produce a massive increase in central sympathetic outflow targeted to both the skeletal muscle and cutaneous circulations; and (2) When abused chronically, cocaine accelerates the aging-related decrease in great vessel distensibility, thereby attenuating sinoaortic baroreflexes. The distinctive features of this proposal include the: (1) use of state-of-the-art techniques (microelectrode recordings of SNA; gated cardiac MRI) to test mechanistic hypotheses in conscious humans; (2) focus on modulation of central sympathetic outflow by cocaine, which traditionally has been viewed as a peripherally-acting sympathomimetic; (3) concept of a synergistic interaction between effects of cocaine and nicotine on the reflex control of SNA; and (4) study of chronic cocaine abusers to directly address the clinical importance of our experimental findings. These studies should fill in some important gaps in our understanding of the underlying mechanisms mediating the sympathomimetic actions of cocaine on the human cardiovascular system.

Agency
National Institute of Health (NIH)
Institute
National Institute on Drug Abuse (NIDA)
Type
Research Project (R01)
Project #
5R01DA010064-08
Application #
6659693
Study Section
Special Emphasis Panel (ZRG1-CCVS (01))
Program Officer
Khalsa, Jagjitsingh H
Project Start
1996-09-15
Project End
2004-08-31
Budget Start
2003-09-01
Budget End
2004-08-31
Support Year
8
Fiscal Year
2003
Total Cost
$253,898
Indirect Cost
Name
University of Texas Sw Medical Center Dallas
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
800771545
City
Dallas
State
TX
Country
United States
Zip Code
75390
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Wilson, Helen W; Widom, Cathy Spatz (2008) An examination of risky sexual behavior and HIV in victims of child abuse and neglect: a 30-year follow-up. Health Psychol 27:149-58
Menon, Dileep V; Wang, Zhongyun; Fadel, Paul J et al. (2007) Central sympatholysis as a novel countermeasure for cocaine-induced sympathetic activation and vasoconstriction in humans. J Am Coll Cardiol 50:626-33
Li, Jia-Ling; Canham, Russell M; Vongpatanasin, Wanpen et al. (2006) Do allelic variants in alpha2A and alpha2C adrenergic receptors predispose to hypertension in blacks? Hypertension 47:1140-6
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Barman, Susan M; Fadel, Paul J; Vongpatanasin, Wanpen et al. (2003) Basis for the cardiac-related rhythm in muscle sympathetic nerve activity of humans. Am J Physiol Heart Circ Physiol 284:H584-97
Crandall, Craig G; Vongpatanasin, Wanpen; Victor, Ronald G (2002) Mechanism of cocaine-induced hyperthermia in humans. Ann Intern Med 136:785-91

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