Abstract
Due to indirect modulation of dopamine transmission, adenosine receptor antagonists may be useful in either treating cocaine use or improving disrupted cognitive-behavioral functions associated with chronic cocaine use. To compare and contrast the stimulant effects of adenosine antagonism to direct dopamine stimulation, we administered 150 mg and 300 mg caffeine, 20 mg amphetamine, and placebo to cocaine-dependent vs. healthy control subjects, matched on moderate caffeine use. Data were obtained on measures of cardiovascular effects, subjective drug effects (ARCI, VAS, DEQ), and a probabilistic reward-learning task sensitive to dopamine modulation. Levels of salivary caffeine and the primary caffeine metabolite paraxanthine were obtained on placebo and caffeine dosing days. Cardiovascular results revealed main effects of dose for diastolic blood pressure and heart rate; follow up tests showed that controls were most sensitive to 300 mg caffeine and 20 mg amphetamine; cocaine-dependent subjects were sensitive only to 300 mg caffeine. Subjective effects results revealed dose × time and dose × group interactions on the ARCI A, ARCI LSD, and VAS ‘elated’ scales; follow up tests did not show systematic differences between groups with regard to caffeine or d-amphetamine. Large between-group differences in salivary paraxanthine (but not salivary caffeine) levels were obtained under both caffeine doses. The cocaine-dependent group expressed significantly higher paraxanthine levels than controls under 150 mg and 3–4 fold greater levels under 300 mg at 90 min and 150 min post caffeine dose. However, these differences also covaried with cigarette smoking status (not balanced between groups), and nicotine smoking is known to alter caffeine/paraxanthine metabolism via cytochrome P450 enzymes. These preliminary data raise the possibility that adenosine antagonists may affect cocaine-dependent and non-dependent subjects differently. In conjunction with previous preclinical and human studies, the data suggest that adenosine modulating drugs may have value in the treatment of stimulant use disorders.
Highlights
Chronic cocaine use results in measurable disruptions in the (DA) dopamine system
We examined reward learning using a task developed by Frank and colleagues, with demonstrated sensitivity to dopamine function, including Parkinson’s disease and administration of cabergolide, haloperidol, and amphetamine [30,31,32,33]
The groups were matched on moderate caffeine consumption in the form of coffee or caffeinated soda, and consumed a reported daily range of caffeine use between 50 mg and 250 mg, based on standard caffeine levels found in one soda and one cup of coffee; salivary caffeine levels did not vary between groups on placebo administration days
Summary
Chronic cocaine use results in measurable disruptions in the (DA) dopamine system. Compounds that directly modulate DA have been considered in cocaine dependence with the aim of regulating DA neurotransmission [2,3], with some laboratory and clinical evidence for efficacy [4,5,6]. It is presently unknown whether compounds that indirectly modulate dopamine will yield efficacy with regard to either reductions in cocaine use, or improvement in cognitive/behavioral processes that are disrupted following chronic cocaine use [7]. Because cocaine may be cross-tolerant with other direct dopamine modulators [8,9], and comprehensive reviews indicate mixed evidence for efficacy [10] indirect modulators should warrant consideration. The manner in which these agents modulate the behavior of stimulant-dependent individuals and healthy non-addicted controls has not been broadly characterized
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