Psychopharmacology (2005) 180: 21–32 DOI 10.1007/s00213-004-2135-9 ORIGINAL INVESTIGATION Jennifer L. Cornish . Jaclyn M. Lontos . Kelly J. Clemens . Iain S. McGregor Cocaine and heroin (‘speedball’) self-administration: the involvement of nucleus accumbens dopamine and μ-opiate, but not δ-opiate receptors Received: 7 April 2004 / Accepted: 22 November 2004 / Published online: 29 January 2005 # Springer-Verlag 2005 Abstract Rationale: The combined administration of heroin and cocaine (‘speedball’) is common among intra- venous drug users. Dopamine receptors in the nucleus ac- cumbens play a key role in cocaine self-administration; however, their role in speedball self-administration is un- known, as is the role of opiate receptors in this region. Objectives: The effect of blocking dopamine D1, D2, μ- opiate or δ-opiate receptors in the nucleus accumbens on the intravenous self-administration of combined heroin and cocaine was examined in rats. Methods: Rats with bilat- eral cannulae implanted into the nucleus accumbens were trained to self-administer intravenous speedball (ratio of cocaine/heroin, 17:1) under a progressive ratio (PR) sched- ule. Prior to their self-administration session, rats were then microinjected with the dopamine D1 receptor antagonist SCH 23390 (1 and 6 nmol side -1 ), the D2 receptor antag- onist raclopride (3 and 10 nmol side -1 ), the μ-opiate re- ceptor antagonist CTOP (0.1, 0.3 and 1.0 nmol side -1 ), the δ-opiate receptor antagonist naltrindole (1.0, 3.0 and 10 nmol side -1 ) or a cocktail of SCH 23390 (1 nmol side -1 ) and CTOP (0.1 nmol side -1 ) into the nucleus accum- bens. Results: Microinjection of SCH 23390, raclopride or CTOP into the nucleus accumbens produced dose-de- pendent decreases in breakpoints under the PR schedule, while naltrindole was without effect. The highest dose of SCH 23390 also significantly reduced locomotor activ- ity measured during speedball self-administration. The combination of SCH 23390 and CTOP significantly re- duced breakpoints, while not affecting locomotor activity. Conclusions: These results indicate that dopamine and μ- opiate receptors, but not δ-opiate receptors, in the nucleus accumbens are involved in the reinforcing effects of speed- ball. Combined administration of D1 and μ-opiate receptor antagonists may be more selective at reducing the rein- forcing effects of speedball self-administration than either drug alone. Keywords Speedball . Cocaine . Heroin . Self- administration . Dopamine . Opiate . Reward . Reinforcement Introduction It is increasingly recognized that drug users typically par- take of many different drugs and that multiple drugs are often consumed within a single session (National Institute on Drug Abuse, 1998). One relatively common drug com- bination involves the simultaneous intravenous administra- tion of cocaine and heroin, commonly referred to as a ‘speedball’ (Schutz et al. 1994). Health and socio-economic problems associated with the use of this drug combination are increasingly recognized and current pharmacotherapies appear largely ineffective in controlling speedball use (see Leri et al. 2003 for review). Previous studies suggest that taking low dose cocaine and heroin in combination may synergistically enhance the reinforcing effects of either drug taken alone (Foltin and Fischman 1992; Hemby et al. 1999). Rats and primates appear more motivated to receive combined heroin/psy- chostimulant infusions relative to cocaine or heroin alone (Ranaldi and Wise 2000; Rowlett et al. 1998). The apparent unique effects produced by combined cocaine and heroin may render current pharmacotherapies, such as methadone- maintenance treatment, relatively ineffective as they target only one drug type (Mendelson and Mello 1996). As such, further investigation may help to establish the neurobio- logical substrates mediating the reinforcing properties of speedball. The mesocorticolimbic dopamine system, projecting from the ventral tegmental area (VTA) to the nucleus ac- cumbens and prefrontal cortex, plays a key role in the reinforcing effects of drugs (Wise 2002). Psychostimu- lants, such as cocaine and amphetamine, affect dopamine uptake transporters, resulting in increases in extracellular J. L. Cornish (*) . J. M. Lontos . K. J. Clemens . I. S. McGregor School of Psychology A19, University of Sydney, 2006 Sydney, Australia e-mail: jcornish@psych.usyd.edu.au Tel.: +61-2-93513544 Fax: +61-2-93518023