The Synergistic Effects of Combining Cocaine and Heroin (“Speedball”) Using a Progressive-Ratio Schedule of Drug Reinforcement

Duvauchelle, Christine L.; Sapoznik, Tova; Kornetsky, Conan

doi:10.1016/s0091-3057(98)00098-7

Cited by 82 publications

(69 citation statements)

References 20 publications

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“…This finding is consistent with observations of synergism between opioids and cocaine in animal models of drug-reinforcement (Rowlett and Woolverton, 1997;Mello et al, 1995;Mattox et al, 1997;Wang et al, 2001;Ranaldi and Munn, 1998;Duvauchelle et al, 1998), drug-discrimination (Suzuki et al, 1997;GreenJordan et al, 2001), analgesia (Nott, 1968;Misra et al, 1987;Sierra et al, 1992;Gatch et al, 1995;Shimada et al, 1988;Kauppila et al, 1992), and drug toxicity (Plunkett et al, 1989;Blumberg and Ikeda, 1978;Leander and Lucot, 1977). The depression in locomotor activity caused by acute, spontaneous withdrawal from heroin was reversed, dose dependently, by cocaine administration.…”

Section: Effects Of Cocaine During Chronic Exposure To Heroin and Dursupporting

confidence: 79%

Effects of Cocaine in Rats Exposed to Heroin

Leri

Flores

Rajabi

et al. 2003

Neuropsychopharmacol

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We investigated whether chronic exposure to heroin alters responses to cocaine in ways that might explain the use of cocaine by opioid addicts. To this end, the effects of cocaine (5 and 20 mg/kg) were assessed on locomotor activity of rats chronically exposed to heroin (0.0, 3.5, 7.0, and 14.0 mg/kg/day, over 14 days, via osmotic mini-pumps), or withdrawn from heroin (1 day, acute withdrawal, and 14 days, protracted withdrawal). Chronic heroin exposure, in itself, dose dependently increased locomotion and acute cocaine administration further elevated locomotor activity in a dose-dependent and additive manner. During acute withdrawal, there was a dosedependent decrease in locomotion that was reversed by cocaine in a dose-dependent manner. During protracted withdrawal, spontaneous locomotion normalized, but rats previously exposed to heroin displayed cross-sensitization to cocaine as indicated by small, but significant, enhanced locomotor response to 5 mg/kg of cocaine, and enhanced intravenous self-administration of low doses of cocaine (0.13 mg/kg/infusion). In a separate study, we measured extracellular dopamine (DA) in the nucleus accumbens (Acb) using in vivo microdialysis before and after acute withdrawal from heroin. During chronic exposure to heroin, basal extracellular DA was elevated dose dependently, whereas in acute withdrawal, levels were not different from those in vehicle-treated rats. In response to cocaine, however, DA activity in the Acb was significantly lower in rats withdrawn from the highest dose of heroin.

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Section: Effects Of Cocaine During Chronic Exposure To Heroin and Dursupporting

confidence: 79%

Effects of Cocaine in Rats Exposed to Heroin

Leri

Flores

Rajabi

et al. 2003

Neuropsychopharmacol

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“…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).…”

Section: Discussionmentioning

confidence: 97%

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

Mello

Negus

2007

Neuropsychopharmacol

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The simultaneous i.v. administration of heroin and cocaine, called a 'speedball,' is often reported clinically, and identification of effective pharmacotherapies is a continuing challenge. We hypothesized that treatment with combinations of a monoamine releaser d-amphetamine, and a mu partial agonist, buprenorphine, might reduce speedball self-administration by rhesus monkeys. Speedballs (0.01 mg/kg/inj cocaine + 0.0032 mg/kg/inj heroin) and food (1 g banana-flavored pellets) were available during four daily sessions on a second-order schedule of reinforcement (fixed ratio (FR)2 (variable ratio (VR)16:S)). Monkeys were treated for 10 days with saline or ascending doses of d-amphetamine (0.0032-0.032 mg/kg/h) + buprenorphine (0.075 or 0.237 mg/kg/day) in combination. d-Amphetamine + both doses of buprenorphine produced an amphetamine dose-dependent decrease in speedball self-administration in comparison to the saline treatment baseline (Po0.01-0.001), but food-maintained responding did not change significantly. d-Amphetamine alone (0.032 mg/kg/h) significantly decreased both food (Po0.01) and speedball-maintained responding (Po0.05). During saline control treatment, speedball unit doses of 0.0032 mg/kg/inj cocaine + 0.001 mg/kg/inj heroin were at the peak of the speedball dose-effect curve. Daily treatment with 0.01 mg/kg/h d-amphetamine + 0.237 mg/kg/day buprenorphine produced a significant downward and rightward shift in the speedball dose-effect curve (Po0.01) and no significant effect on food-maintained responding. A significant decrease in speedball self-administration was sustained over 10 days of treatment. These findings are consistent with our previous reports and suggest that medication mixtures designed to target both the stimulant and the opioid component of the speedball may be an effective approach to polydrug abuse treatment.

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“…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). Clearly, additional research will be required to examine the generality of this speculation, both with drugs of similar and different mechanisms of action.…”

Section: Discussionmentioning

confidence: 99%

“…Other studies provided evidence for a significant interaction between stimulants and opioids in drug self-administration. Some have reported an increase in potency of the combination relative to either drug alone (Duvauchelle et al 1998;Rowlett and Woolverton 1997;Rowlett et al 1998;Winger et al 2006), while other results support the conclusion the that the reinforcing effects of a stimulant/opioid combination are enhanced relative to either drugs alone (Ranaldi and Munn 1998;Wang et al 2001). One conclusion that is possible from these experiments and that would be consistent with the drug self-administration literature is that the effects of a drug combination depend upon the conditions of availability (Ward et al 2005).…”

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confidence: 94%

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

et al. 2007

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Rationale-Abuse of drug mixtures is common. Drug interactions that are super-additive in terms of reinforcing effects may contribute to this phenomenon. Although quantitative methods for assessing drug interactions have been developed, they have not been widely applied to the analysis of reinforcing effects.Objectives-The present experiment was designed to study self-administration of mixtures of drugs with comparable pharmacological mechanisms of action. Our hypothesis was that the drugs would be dose-additive.Materials and methods Rhesus-monkeys prepared with i.v. catheters were allowed to selfadminister cocaine or saline under a progressive-ratio schedule in baseline sessions. When responding was stable, two mu opioid agonists, alfentanil and remifentanil, were tested alone in one group (n=5). Two dopamine (DA) uptake blockers, cocaine and RTI-117 were tested in the other group (n=6). Next, mixtures of doses of the two opioids or the two DA uptake blockers were © Springer-Verlag 2007 Correspondence to: W.L. Woolverton, wwoolverton@psychiatry.umsmed.edu. NIH Public AccessAuthor Manuscript Psychopharmacology (Berl). Author manuscript; available in PMC 2011 June 7.Published in final edited form as:Psychopharmacology (Berl). 2008 March ; 196(4): 575-582. doi:10.1007/s00213-007-0991-9. NIH-PA Author Manuscript NIH-PA Author ManuscriptNIH-PA Author Manuscript tested in approximate 1:1, 1:2, and 2:1 ratios of their ED 50 s. Results were analyzed using isobolographic techniques.Results-All drugs alone and drug mixtures functioned as positive reinforcers in a dose-related manner. There was no difference between experimentally determined ED 50 values and predicted additive ED 50 values for any mixture. Maximum responding maintained by mixtures, a measure of reinforcing strength, did not differ from that for single drugs.Conclusions-Mixtures of various proportions of two drugs with comparable mechanisms of action were additive, i.e., they did not interact. This result will serve as the basis for comparison to studies of mixtures of drugs with various mechanisms of action. KeywordsDrug abuse; Self-administration; Rhesus monkey; Opioid; Dopamine uptake blocker; Drug mixture; Isobologram; Additivity Abuse of drug mixtures is common. Mechanisms that have been advanced to account for polydrug abuse include interactions that enhance positive effects or diminish negative effects of one or more of the combined drugs (Ellinwood et al. 1976;Kosten et al. 1986;Kreek 1987). Several drug combinations have been studied in the laboratory in humans and non-humans under a variety of conditions, including ethanol/barbiturate (DeNoble et al. 1985;Meisch and Lemaire 1990), cocaine/marijuana (Foltin and Fischman 1990), benzodiazepine/caffeine (Rush et al. 1994), ethanol/cocaine (Ikegami et al. 2002), ethanol/marijuana (Liguori et al. 2002, and dextromethorphan/diphenhydramine (Jun et al. 2003). It is not always clear, however, whether and how results can be accounted for by these broad mechanisms. Even for the stimulant/opioid m...

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The Synergistic Effects of Combining Cocaine and Heroin (“Speedball”) Using a Progressive-Ratio Schedule of Drug Reinforcement

Cited by 82 publications

References 20 publications

Effects of Cocaine in Rats Exposed to Heroin

Effects of Cocaine in Rats Exposed to Heroin

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

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

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