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Date of Award


Document Type

Thesis - Pacific Access Restricted

Degree Name

Master of Science (M.S.)


Physiology and Pharmacology

First Advisor

Edward Avakian

First Committee Member

Marvin H. Malone

Second Committee Member

Herschel G. Frye


Cocaine, the principal biologically active alkaloid of Erythroxylon coca, acts as both a local anesthetic agent and an indirect-acting sympathomimetic. These two very different activities make research on and subsequent interpretation of cocaine's multiplicity of varied effects difficult. Not surprisingly, investigations into the central effects of cocaine have yielded mixed results. However, there is a certain body of evidence which points to the euphoric and self-administrating properties of cocaine as appearing to involve the acute activation of central dopamine neuronal systems . With chronic cocaine use, central neurotransmitter alterations have been observed to occur. Dopamine depletion has been hypothesized to result from the overstimulation of these central neurons and the excessive synaptic metabolism of the neurotransmitter. This depletion may underlie the dysphoric aspects of cocaine abstinence and cravings. The potential cardiotoxicity of chronic cocaine abuse has been welldocumented. The possible mechanisms for this remain unclear. The present study was designed to evaluate the effects of repeated daily administration of two different doses (15 and 30 mg/kg/day) of cocaine on male Sprague-Dawely rat cardiac norepinephrine levels. Seven time intervals of sustained dosing were acute (1 dose), 1, 2, 4, 8, 12 and 20 weeks. The catecholamine levels of the whole heart were measured using an HPLC with electrochemical detection. Cardiac norepinephrine levels were unaffected by an acute injection of either cocaine dose. The lower dose elicited a slight increase of 5.8% while the higher dose evoked a small decrease at the 1 week administration period. At 2, 4, and 8 weeks cardiac neurotransmitter levels decreased an average of 13% compared to control values for both doses. At 20 weeks, the catecholamine content was similar to that of the controls. It was observed that cocaine in regard to cardiac norepinephrine content failed to elicit a dose-dependent response. The lower dose of 15 mg/kg/day evoked a greater reduction than that of the higher dose, especially at the 12 week time increment ( -23% and -11%, respectively) which was statistically significant. This is one of the first studies to investigate the effects that repeated daily cocaine dosing has on cardiovascular biochemical pharmacology. It is difficult to postulate the possible etiology and functionality of this decrease. Previous studies have indicated that cocaine might cause alterations in tyrosine hydroxylase activity, the rate-limiting enzyme in the biosynthesis of catecholamines which could be responsible for the reduction observed.



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