Self-Administered Heroin and Cocaine Combinations in the Rat: Additive Reinforcing Effects—Supra-Additive Effects on Nucleus Accumbens Extracellular Dopamine

Abstract

The concurrent use of cocaine and opiate combinations (speedball) has increased since the 1970s and now represents a growing subset of intravenous drug abusers. An isobolographic analysis was applied to the ascending limb of the dose-effect curves for rat selfadministration of cocaine, heroin, and their combination to determine the nature of the interaction. The addition of heroin to cocaine shifted the dose-effect curve for self-administration to the left, and the modulation in reinforcing efficacy of the combination of cocaine and heroin was found to be additive. A second experiment used microdialysis to determine the effects of this drug combination on nucleus accumbens (NAc) extracellular levels of dopamine ([DA] e ) in rats self-administering low doses of cocaine, heroin, or cocaine/ heroin combinations. These doses of cocaine and cocaine/heroin combinations significantly increased NAc [DA] e , while heroin alone did not. The ratio of the % baseline of [DA] e (or the dialysate concentrations of DA) to cocaine in the dialysate was higher during selfadministration of cocaine/heroin combinations than with cocaine alone. These data indicate that although the interaction between cocaine and heroin in maintaining self-administration is additive, a potentiation of NAc dopaminergic neurotransmission is present, suggesting that NAc [DA] e may not be a direct measure of reinforcing efficacy and/or it is not central to the mediation of the selfadministration of this drug combination.

Effects of d-Amphetamine and Buprenorphine Combinations on Speedball (Cocaine+Heroin) Self-Administration by Rhesus Monkeys

“…In rhesus monkeys and in rodents, combinations of cocaine and mu opioids appear to be more reinforcing than either component drug alone under most (Mattox et al, 1997;Rowlett and Woolverton, 1997;Duvauchelle et al, 1998;Ranaldi and Munn, 1998;David et al, 2001;Wang et al, 2001;Rowlett et al, 2005;Smith et al, 2006;Winger et al, 2006) but not all conditions Hemby et al, 1996;Ward et al, 2005). For example, cocaine and heroin at unit doses that did not maintain self-administration alone were significantly more reinforcing than saline when combined in a speedball in rhesus monkeys (Rowlett and Woolverton, 1997;Rowlett et al, 2005).…”

“…In addition, microdialysis studies in rats indicate that cocaine + heroin mixtures increase levels of extracellular dopamine significantly above levels measured after cocaine or heroin alone (Hemby et al, 1999). Another microdialysis study found that a cocaine + heroin combination produced supra-additive effects on extracellular dopamine from the nucleus accumbens in comparison to heroin alone (Smith et al, 2006).…”

Self-administration of drug mixtures by monkeys: combining drugs with comparable mechanisms of action

“…It may be that super-additivity as reinforcers is confined to drugs with different mechanisms action. On the other hand, this is not always the case, as both additivity and sub-additive interactions have been reported for self-administration of mixtures of cocaine and drugs with different mechanisms of action (Negus 2005;Rowlett et al 2007;Smith et al 2006). For the combination of heroin and cocaine, increases in maximum responding under a PR schedule, a measure of increased reinforcing strength, have been reported in some cases (Duvauchelle et al 1998;Ranaldi and Munn 1998) but not in others (Rowlett and Woolverton 1997;Ward et al 2005).…”

“…Super-additivity was not observed. Smith et al (2006) also reported additivity between cocaine and heroin in rats. Although these experiments suggest that this is a viable approach to studying the self-administration of drug combinations, it has not been systematically investigated with regard to reinforcing effects.…”

Microdialysis with Radiometric Monitoring of L-[β-11C]DOPA to Assess Dopaminergic Metabolism: Effect of Inhibitors of L-Amino Acid Decarboxylase, Monoamine Oxidase, and Catechol-O-Methyltransferase on Rat Striatal Dialysate

“…Dopamine (DA) is a catecholamine involved in neuropsychiatric disorders such as Parkinson's disease (Hornykiewicz and Kish, 1987), schizophrenia (Lindstrom et al, 1999), Alzheimer's disease (Itoh et al, 1996), epilepsy (Smolders et al, 1997), attention deficit hyperactivity disorder (Ernst et al, 1998), as well as drug dependence (Smith et al, 2006). Dopamine is generated from 3,4-dihydroxy-L-phenylalanine (L-DOPA) by aromatic L-amino acid decarboxylase (AADC).…”