Investigating cocaine/heroin interactions in rats: From neural mechanisms of reinforcement to modeling polydrug histories

While the concomitant use of cocaine and heroin is substantial and has negative consequences on health and outcome of opioid-addiction treatment, the pharmacological reasons for this co-use are poorly understood. Cocaine may be co-used with opioids to achieve enhanced subjective effects, but clinical experimental evidence is lacking. The subjective effects of cocaine also appear to be enhanced in opioid-dependent users. Additionally, results from preclinical studies designed to test these hypotheses remain equivocal.; Chapter 1 highlights how poorly understood human cocaine/heroin co-use patterns are, stressing that application of this information is needed to design appropriate procedures to study cocaine/heroin self-administration preclinically. This chapter outlines the three distinct approaches employed to study the pharmacology of this co-use in the present thesis.; Enhancement of cocaine's effects by heroin suggests underlying neurobiological interactions. Studies described in Chapter 2 and Appendix i revealed that antagonism of mu-opioid receptors in the nucleus accumbens and ventral tegmental area decreased cocaine self-administration under a PR but not FR schedule. Additionally, blockade of delta-opioid receptors in both brain regions appeared to affect cocaine-maintained responding as well.; One typical co-use pattern involves the simultaneous administration of the two drugs, referred to as a "speedball". In Chapter 3, speedball self-administration was evaluated in rats using both a PR schedule and a choice procedure. Under the PR schedule, speedball did not support higher responding than cocaine alone. Using a choice procedure, however, a preference was demonstrated for speedball over cocaine alone.; Perhaps more common is concurrent but intermittent use of both cocaine and heroin. In Chapter 4 we demonstrate that a history of heroin self-administration can greatly impact cocaine's reinforcing effects during subsequent self-administration sessions.; Overall, these results indicate that cocaine/heroin co-use can produce behavioral effects different from cocaine alone, perhaps in part explaining this co-use in humans. However these effects are only present under certain experimental conditions. Interpretation of this observation will be strengthened by not only an increased knowledge of cocaine/heroin use in humans, but an expansion of preclinical tools, such as novel self-administration procedure designed to investigate the behavioral and pharmacological effects of this drug combination.