Abstract
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 an opioid alternative 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 fixed-ratio (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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References
Bakeman R (2005) Recommended effect size statistics for repeated measures designs. Behav Res Methods 37:379–384. doi:10.3758/BF03192707
Beardsley PM, Aceto MD, Cook CD, Bowman ER, Newman JL, Harris LS (2004) Discriminative stimulus, reinforcing, physical dependence, and antinociceptive effects of oxycodone in mice, rats, and rhesus monkeys. Exp Clin Psychopharm 12:163–172. doi:10.1037/1064-1297.12.3.163
Bernstein KT, Bucciarelli A, Piper TM, Gross C, Tardiff K, Galea S (2007) Cocaine- and opiate-related fatal overdose in New York City, 1990-2000. BMC Public Health 7:31. doi:10.1186/1471-2458-7-31
Bux DA, Lamb RJ, Iguchi MY (1995) Cocaine use and HIV risk behavior in methadone maintenance patients. Drug Alcohol Depend 37:29–35. doi:10.1016/0376-8716(94)01058-S
Coffin PO, Galea S, Ahern J, Leon AC, Vlahov D, Tardiff K (2003) Opiates, cocaine and alcohol combinations in accidental drug overdose deaths in New York City, 1990-1998. Addiction 98:739–747. doi:10.1046/j.1360-0443.2003.00376.x
DeMaria PA, Sterling R, Weinstein SP (2000) The effect of stimulant and sedative use on treatment outcome of patients admitted to methadone maintenance treatment. Am Acad Addict Psychiatry 9:145–153. doi:10.1080/10550490050173217
Downey KK, Helmus TC, Schuster CR (2000) Treatment of heroin-dependent poly-drug abusers with contingency management and buprenorphine maintenance. Exp Clin Psychopharm 8:176–184. doi:10.1037//1064-1297.8.2.176
Duvauchelle CL, Sapoznik T, Kornetsky C (1998) The synergistic effects of combining cocaine and heroin (“Speedball”) using a progressive-ratio schedule of drug reinforcement. Pharmacol Biochem Behav 61:297–302. doi:10.1016/S0091-3057(98)00098-7
Epstein DH, Schmittner J, Umbricht A, Schroeder JR, Moolchan ET, Preston KL (2009) Promoting abstinence from cocaine and heroin with a methadone dose increase and a novel contingency. Drug Alcohol Depend 101:92–100. doi:10.1016/j.drugalcdep.2008.11.006
Foltin RW, Fischman MW (1992) The cardiovascular and subjective effects of intravenous cocaine and morphine combinations in humans. J Pharmacol Exp Ther 261:623–632
Freeman KB, Woolverton WL (2009) Self-administration of cocaine and nicotine mixtures by rhesus monkeys. Psychopharmacol 207:99–106. doi:10.1007/s00213-009-1637-x
Freeman KB, Woolverton WL (2011) Self-administration of cocaine and remifentanil by monkeys: choice between single drugs and mixtures. Psychopharmacol 215:281–290. doi:10.1007/s00213-010-2131-1
Freeman KB, Naylor JE, Prisinzano TE, Woolverton WL (2014) Assessment of the kappa opioid agonist, salvinorin A, as a punisher of drug self-administration in monkeys. Psychopharmacol. doi:10.1007/s00213-014-34436-2
Glass PSA, Gan TJ, Howell S (1999) A review of the pharmacokinetics and pharmacodynamics of remifentanil. Anesth Analg 89:7. doi:10.1097/00000539-199910001-00003
Grella CE, Anglin MD, Wugalter SE (1995) Cocaine and crack use and HIV risk behaviors among high-risk methadone maintenance clients. Drug Alcohol Depend 37:15–21. doi:10.1016/0376-8716(94)01059-T
Harrigan SE, Downs DA (1978) Self-administration of heroin, acetylmethadol, morphine, and methadone in rhesus monkeys. Life Sci 22:619–623. doi:10.1016/0024-3205(78)90342-9
Hursh SR, Silberberg A (2008) Economic demand and essential value. Psychol Rev 115:186–198. doi:10.1037/0033-295X.115.1.186
Iglauer C, Woods JH (1974) Concurrent performance: reinforcement by different doses of intravenous cocaine in rhesus monkeys. J Exp Anal Behav 22:179–196. doi:10.1901/jeab.1974.22.179
Joe GW, Simpson DD (1995) HIV risks, gender, and cocaine use among opiate users. Drug Alcohol Depend 37:23–28. doi:10.1016/0376-8716(94)01030-O
Johanson CE, Schuster CR (1975) A choice procedure for drug reinforcers: cocaine and methylphenidate in the rhesus monkey. J Pharmacol Exp Ther 193:676–688
Leri F, Bruneau J, Stewart J (2003) Understanding polydrug use: review of heroin and cocaine co-use. Addiction 98:7–22. doi:10.1046/j.1360-0443.2003.00236.x
Lynch WJ, Carroll ME (2001) Regulation of drug intake. Exp Clin Psychopharmacol 9:131–143. doi:10.1037//1064-1297.9.2.131
Magura S, Nwakeze PC, Demsky S (1998) Pre- and in-treatment predictors of retention in methadone treatment using survival analysis. Addiction 93:51–60. doi:10.1046/j.1360-0443.1998.931516.x
Mattox AJ, Thompson SS, Carroll ME (1997) Smoked heroin and cocaine base (speedball) combinations in rhesus monkeys. Exp Clin Psychopharmacol 5:113–118. doi:10.1037/1064-1297.5.2.113
Negus SS (2005) Interactions between the reinforcing effects of cocaine and heroin in a drug-vs-food choice procedure in rhesus monkeys: a dose-addition analysis. Psychopharmacol 180:115–124. doi:10.1007/s00213-004-2133-y
Pickents R, Thompson T (1968) Cocaine-reinforced behavior in rats: effects of reinforcement magnitude and fixed-ratio size. J Pharmacol Exp Ther 161:122–129
Preston KL, Sullivan JT, Strain EC, Bigelow GE (1996) Enhancement of cocaine’s abuse liability in methadone maintenance patients. Psychopharmacol 123:15–25. doi:10.1007/BF02246276
Ranaldi R, Munn E (1998) Polydrug self-administration in rats: cocaine-heroin is more rewarding than cocaine-alone. Neuro Rep 9:2463–2466. doi:10.1097/00001756-199808030-00007
Rowlett JK, Woolverton WL (1997) Self-administration of cocaine and heroin combinations by rhesus monkeys responding under a progressive-ratio schedule. Psychopharmacol 133:363–371. doi:10.1007/s002130050415
Rowlett JK, Wilcox KM, Woolverton WL (1998) Self-administration of cocaine-heroin combinations by rhesus monkeys: antagonism by naltrexone. J Pharmacol Exp Ther 286:61–69
Rowlett JK, Rodefer JS, Spealman RD (2005) Self-administration of cocaine-opioid combinations by rhesus monkeys: evaluation of the role of μ receptor efficacy using labor supply analysis. J Pharmacol Exp Ther 312:1289–1287. doi:10.1124/jpet.104.076646
Rowlett JK, Platt DM, Yao WD, Spealman RD (2007) Modulation of heroin and cocaine self-administration by dopamine D1- and D2-like receptor agonists in rhesus monkeys. J Pharmacol Exp Ther 321:1135–1143. doi:10.1124/jpet.107.120766
Stine SM, Freeman M, Burns B, Charney DS, Kosten T (1992) Effect of methadone dose on cocaine abuse in a methadone program. Am J Addict 1:294–303. doi:10.1111/j.1521-0391.1992.tb00355.x
Wade-Galuska T, Winger G, Woods JH (2007) A behavioral economic analysis of cocaine and remifentanil self-administration in rhesus monkeys. Psychopharmacol 194:563–572. doi:10.1007/s00213-007-0858-0
Walsh SL, Sullivan JT, Preston KL, Garner JE, Bigelow GE (1996) Effects of naltrexone on response to intravenous cocaine, hydromorphone and their combination in humans. J Pharmacol Exp Ther 279:524–538
Wang NS, Brown VL, Grabowski J, Meisch RA (2001) Reinforcement by orally delivered methadone, cocaine, and methadone-cocaine combinations in rhesus monkeys: are the combinations better reinforcers? Psychopharmacol 156:63–72. doi:10.1007/s002130100731
Ward SJ, Morgan D, Roberts DCS (2005) Comparison of the reinforcing effects of cocaine and cocaine/heroin combinations under progressive ratio and choice schedules in rats. Neurospychopharmacol 30:286–295. doi:10.1038/sj.npp.1300560
Wilson MC, Hitomi M, Schuster CR (1971) Psychomotor stimulant self administration as a function of dosage per injection in the rhesus monkey. Psychopharmacol 22:271–281. doi:10.1007/BF00401789
Winger G, Galuska CM, Hursh SR, Woods JH (2006) Relative reinforcing effects of cocaine, remifentanil, and their combination in rhesus monkeys. J Pharmacol Exp Ther 318:223–229. doi:10.1124/jpet.105.100461
Woolverton WL, Wang Z, Vasterling T, Tallarida R (2008) Self-administration of cocaine-remifentanil mixtures by monkeys: an isobolographic analysis. Psychopharmacol 198:387–394. doi:10.1007/s00213-008-1152-5
Woolverton WL, Freeman KB, Myerson J, Green L (2012) Suppression of cocaine self-administration in monkeys: effects of delayed punishment. Psychopharmacol 220:509–517. doi:10.1007/s00213-011-2501-3
Acknowledgments
This research was supported by the National Institute on Drug Abuse grant R01 DA-019471 to W.L.W. The authors would like to gratefully thank Steven Ross for his technical assistance.
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The authors have no conflicts of interest to disclose.
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Huskinson, S.L., Freeman, K.B. & Woolverton, W.L. Self-administration of cocaine and remifentanil by monkeys under concurrent-access conditions. Psychopharmacology 232, 321–330 (2015). https://doi.org/10.1007/s00213-014-3661-8
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DOI: https://doi.org/10.1007/s00213-014-3661-8