Previous investigations have shown that recurrent exposure to dietary lead or cadmium results in an attenuated response to ip injections of cocaine HCL. Specifically, these metals reduced the psychostimulant effects of a 10mg/kg dose of cocaine HCL, but not a 20 or 40 mg/kg dose, in adult male rats. Because lead and cadmium are competitive with calcium, and inasmuch as calcium-mediation is central to the neurochemical and behavioral effects of cocaine, it is possible that these toxicants may attenuate the pharmacologic effects of cocaine. Relevant to this issue, four separate lines of investigation are proposed. Experiments 1 and 2 will examine the effects of chronic low- level exposure to lead or cadmium on the rate-dependent effects of acute cocaine exposure, in an operant context. The second series of experiments will assess the impact of lead (Exp. 3) or cadmium (Exp. 4) on the discriminative stimulus effects associated with cocaine. Experiments 5 and 6 will test for the rewarding effects of cocaine in lead-treated and cadmium-treated animals, using an intravenous self- administration paradigm. Also, the effects of lead (Exp. 7) or cadmium (Exp. 8) on cocaine-induced increases in extracellular levels of dopamine within the nucleus accumbens and prefrontal cortex will be determined, using a microdialysis technique. Finally, the effect of lead or cadmium on cocaine pharmacokinetics will be assessed (Exp. 9-10). In all experiments a full range of drug doses will be used. The results from this project will provide valuable information about the possible link between xenobiotic contamination and the response to a prominently abused psychoactive drug.
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