Assessment of noradrenergic mediation of the aversive effects of cocaine

The propensity to self-administer cocaine may be a function of both its positively reinforcing and aversive effects, with the latter acting as a limiting factor on overall drug-taking. And although the anatomical and neurochemical substrates for cocaine's positively reinforcing effects have been well characterized, relatively little is known about the physiological underpinnings of its aversive effects. Cocaine is a non-selective inhibitor of the three monoamine neurotransmitters dopamine, norepinephrine and serotonin, the first of which appears to be the predominant system mediating cocaine's positively reinforcing effects. To better characterize the relative roles of these systems in the induction of cocaine's aversive effects, the current assessments examined cocaine and other monoaminergic compounds in the conditioned taste aversion (CTA) preparation. Specifically, in Experiment 1, cocaine was compared to three reuptake inhibitors, each possessing relative specificity for one of the three monoamine transporters, in their ability to induce CTAs. Rats were given access to a novel saccharin solution and injected with either cocaine, GBR 12909, desipramine or clomipramine at one of three doses (18, 32 and 50 mg/kg). Desipramine generally induced stronger aversions than GBR 12909 and clomipramine and was the only compound that matched cocaine's aversion acquisition function at all doses (although all compounds conditioned some degree of aversion), suggesting that the noradrenergic system may be the largest monoaminergic contributor to cocaine's aversive effects. To further clarify a role for the this system, cocaine-induced CTAs (10, 18 and 32 mg/kg) were conducted under conditions of antagonism at the norepinephrine alpha1 and beta receptors using prazosin (0.3 mg/kg; Experiment 3) and propranolol (10 mg/kg; Experiment 4), respectively, at doses that were determined to be non-aversive in the CTA preparation (Experiment 2). In each case of noradrenergic antagonism, there was no diminishment in the aversions conditioned with cocaine, suggesting that these effects are mediated by non-noradrenergic NT activity. Furthermore, prazosin and propranolol administration appeared to facilitate the conditioned aversive effects of cocaine. The implications of these findings in regards to other monoaminergic processes are discussed.