The specific aims of our research have been derived from the findings that we have made during the first two and one-half years of NIDA support to study""""""""Cardiorespiratory Effects of Cocaine"""""""" Our first aim will be to continue in our pursuit of characterizing the effects of cocaine on the sympathetic nervous system. Hypotheses that will be tested are that cocaine administration: (1) in i.v. doses of 0.0625 to 0.25 mg/kg will augment the effects of cardiac sympathetic nerve stimulation on the heart; however, doses above 2 mg/kg and above will not exhibit an augmenting effect; (2) will result in inhibition of central sympathetic outflow to the heart; and the site of this effect is the ventrolateral medulla (subretrofacial nucleus); (3) will result in inhibition of ganglionic transmission due to inhibition of norepinephrine uptake in the ganglia; (4) will result in selective stimulation of the adrenal medulla, leading to an increase in plasma epinephrine levels; (5) will result in sympathetically- mediated contraction of the isolated coronary artery, as well as sympathetically-mediated release of endothelial relaxing factor; (6) will result in tachyphylaxis to the sympathomimetic effects of the drug and the tachyphylaxis will e reversible after blockade of presynaptic alpha2- adrenoceptors; and (7) in repeated doses over a period of several hours (""""""""run"""""""") will result in down regulation of adrenoceptors.
Our second aim will be to continue in our pursuit of characterizing the direct effects of cocaine on cardiac and neural tissues. Hypotheses that will be tested are that: (1) cocaine's direct effects on the heart resemble more closely the drug flecainide than the drug lidocaine; (2) cocaine acts directly on cardiac tissue to counteract Ca2+ entry into A-V nodal cells; and (3) cocaine's direct negative inotropic effect is not counteracted by its sympathomimetic effect.
Our third aim i s to determine whether ethanol and nicotine as well as interference with the activity of plasma cholinesterase will predispose subjects to cocaine-cardiotoxicity.
Our fourth aim will be to use information obtained from pursuing Aims 1-3 as a basis for developing drugs that would prevent and/or counteract cardiovascular disorders associated with cocaine abuse. We will also determine whether any deleterious actions occur on the cardiovascular system when drugs that are proposed to interfere with drug taking behavior (e.g., tricyclic experimental animals using standard techniques that are for the most part on-going in our laboratories. Our findings will provide: (1) new information on the pharmacology of cocaine, and information on nay deleterious effects that might occur when drugs which might interfere with drug taking behavior are combined with cocaine. (2) a rationale basis for selecting drugs to counter neurocardiovascular effects of the drug.

Agency
National Institute of Health (NIH)
Institute
National Institute on Drug Abuse (NIDA)
Type
Research Project (R01)
Project #
5R01DA005333-08
Application #
2117573
Study Section
Drug Abuse Biomedical Research Review Committee (DABR)
Project Start
1987-09-30
Project End
1995-08-31
Budget Start
1994-09-01
Budget End
1995-08-31
Support Year
8
Fiscal Year
1994
Total Cost
Indirect Cost
Name
Georgetown University
Department
Pharmacology
Type
Schools of Dentistry
DUNS #
049515844
City
Washington
State
DC
Country
United States
Zip Code
20057
Dickerson, L W; Rodak, D J; Kuhn, F E et al. (1999) Cocaine-induced cardiovascular effects: lack of evidence for a central nervous system site of action based on hemodynamic studies with cocaine methiodide. J Cardiovasc Pharmacol 33:36-42
Dickerson, L W; Rodak, D J; Fleming, T J et al. (1998) Parasympathetic neurons in the cranial medial ventricular fat pad on the dog heart selectively decrease ventricular contractility. J Auton Nerv Syst 70:129-41
Massari, V J; Dickerson, L W; Gray, A L et al. (1998) Neural control of left ventricular contractility in the dog heart: synaptic interactions of negative inotropic vagal preganglionic neurons in the nucleus ambiguus with tyrosine hydroxylase immunoreactive terminals. Brain Res 802:205-20
Blinder, K J; Dickerson, L W; Gray, A L et al. (1998) Control of negative inotropic vagal preganglionic neurons in the dog: synaptic interactions with substance P afferent terminals in the nucleus ambiguus? Brain Res 810:251-6
Dickerson, L W; Panico, W H; Kuhn, F E et al. (1997) Stimulation of dog RVLM and A5 area changes sympathetic outflow to vascular beds without effect on the heart. Am J Physiol 272:R821-39
Hernandez, Y M; Raczkowski, V F; Dretchen, K L et al. (1996) Cocaine inhibits sympathetic neural activity by acting in the central nervous system and at the sympathetic ganglion. J Pharmacol Exp Ther 277:1114-21
Gillis, R A; Hernandez, Y M; Erzouki, H K et al. (1995) Sympathetic nervous system mediated cardiovascular effects of cocaine are primarily due to a peripheral site of action of the drug. Drug Alcohol Depend 37:217-30
Uszenski, R T; Gillis, R A; Schaer, G L et al. (1992) Additive myocardial depressant effects of cocaine and ethanol. Am Heart J 124:1276-83
Kuhn, F E; Gillis, R A; Virmani, R et al. (1992) Cocaine produces coronary artery vasoconstriction independent of an intact endothelium. Chest 102:581-5
Gillis, R A; Bachenheimer, L C; Dretchen, K L et al. (1991) Role of the sympathetic nervous system in the cardiovascular effects of cocaine. NIDA Res Monogr 108:92-109

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