![]() It is not clear how well these data generalize to caffeine effects in individuals who abuse cocaine. In non-cocaine dependent subjects trained to discriminate cocaine, oral caffeine produced discrimination of cocaine-like effects however, cocaine was administered in oral preparation and at low doses. īecause adenosine modulation of DA is indirect, and because cocaine-dependence alters DA transmission and reward processing, adenosine antagonists may reveal unique psychopharmacological effects compared to direct DA modulators in cocaine-dependent subjects relative to non-stimulant using controls. have reported that both A 1 receptor antagonists and paraxanthine (the primary metabolite of caffeine) have unique neurobiological and behavioral interactions with DA transmission. The A 2A receptor antagonist SYN115 produced modest stimulant-like subjective effects and enhanced fMRI-measured BOLD response in the orbital frontal cortex. Adenosine A 1 and A 2 antagonists have been suggested as potential pharmacotherapies in both substance abuse and Parkinson’s disease. Subsequently, the manner in which these agents modulate the behavior of stimulant-dependent individuals and healthy non-addicted controls has not been broadly characterized.Ĭaffeine is a mixed A 1 and A 2 receptor antagonist that appears to modulate dopamine function at both presynaptic and postsynaptic sites. Within-subject comparison of the psychopharmacological and cardiovascular effects of both direct and indirect modulators has not been extensive. ![]() Because cocaine may be cross-tolerant with other direct dopamine modulators, and comprehensive reviews indicate mixed evidence for efficacy indirect modulators should warrant consideration. 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. Accordingly, compounds that directly modulate DA have been considered in cocaine dependence with the aim of regulating DA neurotransmission, with some laboratory and clinical evidence for efficacy. Allostatic shifts in neural and behavioral systems result in neurobehavioral states that foster continued use and relapse. 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.Ĭhronic cocaine use results in measurable disruptions in the (DA) dopamine system. These preliminary data raise the possibility that adenosine antagonists may affect cocaine-dependent and non-dependent subjects differently. 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. 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. Large between-group differences in salivary paraxanthine (but not salivary caffeine) levels were obtained under both caffeine doses. 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. 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. Levels of salivary caffeine and the primary caffeine metabolite paraxanthine were obtained on placebo and caffeine dosing days. Data were obtained on measures of cardiovascular effects, subjective drug effects (ARCI, VAS, DEQ), and a probabilistic reward-learning task sensitive to dopamine modulation. ![]() ![]() healthy control subjects, matched on moderate caffeine 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. 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.
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