Self-administration of cocaine–remifentanil mixtures by monkeys: an isobolographic analysis

Woolverton, William L.; Wang, Zhixia; Vasterling, Theresa; Tallarida, Ronald J.

doi:10.1007/s00213-008-1152-5

Cited by 24 publications

(38 citation statements)

References 28 publications

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“…Also, a rather cumbersome notation used by Loewe seems to have prevented a clear understanding of its basis and that fact may account for its initial limited application. 23,24 in which various combinations including cocaine and remifentanil were examined in protocols involving self-administration in monkeys. Tanda et al 25 examined combinations of cocaine and other dopamine uptake inhibitors in mice.…”

Section: Dose Equivalencementioning

confidence: 99%

Quantitative Methods for Assessing Drug Synergism

2011

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Two or more drugs that individually produce overtly similar effects will sometimes display greatly enhanced effects when given in combination. When the combined effect is greater than that predicted by their individual potencies, the combination is said to be synergistic. A synergistic interaction allows the use of lower doses of the combination constituents, a situation that may reduce adverse reactions. Drug combinations are quite common in the treatment of cancers, infections, pain, and many other diseases and situations. The determination of synergism is a quantitative pursuit that involves a rigorous demonstration that the combination effect is greater than that which is expected from the individual drug's potencies. The basis of that demonstration is the concept of dose equivalence, which is discussed here and applied to an experimental design and data analysis known as isobolographic analysis. That method, and a related method of analysis that also uses dose equivalence, are presented in this brief review, which provides the mathematical basis for assessing synergy and an optimization strategy for determining the dose combination.

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Section: Dose Equivalencementioning

confidence: 99%

Quantitative Methods for Assessing Drug Synergism

2011

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“…Several studies have used progressive-ratio (PR) schedules of reinforcement which allow assessment of both the potency and effectiveness (as measured by breakpoint) of a reinforcer in a single assay (for reviews see Arnold and Roberts 1997; Rowlett 2000; Stafford et al 1998). Cocaine–opioid combinations have been studied in both rodents (Duvachelle et al 1998; Ranaldi and Munn 1998; Ward et al 2005) and non-human primates (Rowlett et al 2005, 2007; Rowlett and Woolverton 1997; Woolverton et al 2008). In five of the seven studies cited above, adding an opioid to cocaine (or vice versa) shifted the dose–response function leftward, suggesting that the cocaine–opioid combination was, under some conditions, a more potent reinforcer than either drug alone (Duvachelle et al 1998; Rowlett et al 2005, 2007; Rowlett and Woolverton 1997; Woolverton et al 2008).…”

Section: Introductionmentioning

confidence: 99%

“…Cocaine–opioid combinations have been studied in both rodents (Duvachelle et al 1998; Ranaldi and Munn 1998; Ward et al 2005) and non-human primates (Rowlett et al 2005, 2007; Rowlett and Woolverton 1997; Woolverton et al 2008). In five of the seven studies cited above, adding an opioid to cocaine (or vice versa) shifted the dose–response function leftward, suggesting that the cocaine–opioid combination was, under some conditions, a more potent reinforcer than either drug alone (Duvachelle et al 1998; Rowlett et al 2005, 2007; Rowlett and Woolverton 1997; Woolverton et al 2008). However, in all cases but one (see Ranaldi and Munn 1998), the asymptotes of the dose–response functions for the combinations were no different from at least one of the component drugs, suggesting that the cocaine–opioid combination was not a more effective reinforcer than either drug alone.…”

Section: Introductionmentioning

confidence: 99%

Self-administration of cocaine and remifentanil by monkeys: choice between single drugs and mixtures

Freeman

Woolverton

2010

Psychopharmacology

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Rationale Cocaine and opioids are often co-abused. As yet, however, there is no clear evidence that the drugs interact to make the mixture a more effective reinforcer. Objective The present study examined the relative reinforcing potency and maximum effectiveness of the cocaine–opioid combination in monkeys given a choice between cocaine–opioid mixtures and the single-component drugs. Method Rhesus monkeys were allowed to choose between injections of cocaine (100 μg/kg/inj) and other doses of cocaine (10–560 μg/kg/inj) or remifentanil (0.03–3.0 μg/kg/inj). A dose-addition model was used to select dose combinations for mixtures of cocaine and remifentanil predicted to be equivalent to 100 μg/kg/inj of cocaine in reinforcing effect if the drugs were additive. The monkeys were then allowed to choose between (a) cocaine and mixtures predicted to be equivalent to 100 μg/kg/inj of cocaine, (b) increasing doses of the mixtures and the single-component drugs, and (c) cocaine or remifentanil at doses that were in the highest safe range. Results Generally, monkeys preferred the mixtures over 100 μg/kg/inj of cocaine, evidence for superadditivity. However, preferences for the mixture ceased when relatively high doses of single-component drugs were offered as alternatives. When doses within the mixture were raised and offered with relatively high doses of the single drugs, there was no clear preference for either option. The highest dose of remifentanil was chosen over the highest dose of cocaine by all monkeys. Conclusion The current results indicate that cocaine–opioid combinations can be super-additive in terms of potency, but are not, at maximum, more effective than the single-component drugs.

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“…Despite the consistent finding that cocaine and opioid combinations are not more effective reinforcers, it is important to note that the combinations are consistently more potent reinforcers than the single drugs (Duvauchelle et al 1998; Freeman and Woolverton 2011; Negus 2005; Ranaldi and Munn 1998; Rowlett et al 1998, 2005, 2007; Rowlett and Woolverton 1997; Ward et al 2005; Woolverton et al 2008). Increased potency indicates that small amounts of cocaine and opioids combined have reinforcing effects similar to one of the drugs at a larger dose.…”

Section: Discussionmentioning

confidence: 99%

“…Results from this approach indicate that cocaine-opioid mixtures were not more effective reinforcers than at least one of the single drugs (Mattox et al 1997; Wade-Galuska et al 2007; Winger et al 2006). In PR studies, where the response requirement systematically increases within session, cocaine-opioid mixtures were more potent reinforcers than the single drugs, evidenced by leftward shifts in the dose-response functions for the mixtures (Duvauchelle et al 1998; Ranaldi and Munn 1998; Rowlett et al 1998, 2005, 2007; Rowlett and Woolverton 1997; Woolverton et al 2008, but see Ward et al 2005). While more potent, cocaine-opioid mixtures were not more effective reinforcers than the single drugs as evidenced by comparable breakpoints for the mixtures and the single drugs (Duvauchelle et al 1998; Rowlett et al 1998, 2005, 2007; Rowlett and Woolverton 1997; Ward et al 2005; Woolverton et al 2008; but see Ranaldi and Munn 1998).…”

Section: Introductionmentioning

confidence: 99%

Self-administration of cocaine and remifentanil by monkeys under concurrent-access conditions

2014

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Rationale Cocaine and opioids are often co-abused. Laboratory research has focused largely on the reinforcing effects of mixtures of drugs relative to the drugs alone. Less research has examined drug mixing by the subject under concurrent-access conditions. Objective Self-administration of various doses of cocaine and remifentanil was examined under concurrent-access conditions. It was hypothesized that if cocaine and opioid combinations were more effective reinforcers than the single drugs, subjects would mix the two drugs by adjusting their responding to cocaine and opioid alternatives to maintain an optimal ratio of cocaine:remifentanil intake. Method Three male rhesus monkeys were allowed to self-administer cocaine (0.05–0.2 mg/kg/inj) or saline on one lever and remifentanil (0.05–0.4 µg/kg/inj) or saline on the other lever under concurrent FR 10 schedules. Daily sessions lasted 2-h, and there was a 1-s timeout after every 10-s injection. Results When saline and drug were concurrently available, responding on the saline-associated lever was low relative to the drug alternative. When cocaine and remifentanil were concurrently available, both drugs were self-administered above saline levels. Cocaine intake decreased and remifentanil intake increased as a function of the remifentanil dose that was available. Conversely, cocaine intake and remifentanil intake did not change systematically as a function of the cocaine dose that was available. Conclusion Monkeys will mix cocaine and an opioid when the two drugs are available concurrently. However, there was no indication that monkeys titrated drug-intake to maintain an optimal ratio of intake of the two compounds.

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Self-administration of cocaine–remifentanil mixtures by monkeys: an isobolographic analysis

Cited by 24 publications

References 28 publications

Quantitative Methods for Assessing Drug Synergism

Quantitative Methods for Assessing Drug Synergism

Self-administration of cocaine and remifentanil by monkeys: choice between single drugs and mixtures

Self-administration of cocaine and remifentanil by monkeys under concurrent-access conditions

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