Discriminative stimulus effects of a cocaine/heroin "speedball" combination in rhesus monkeys

J Pharmacol Exp Ther. 1998 Jun;285(3):1123-36.


Cocaine and heroin often are abused together in a combination known as a "speedball," but relatively little is known about ways in which cocaine and heroin may interact to modify each other's abuse-related effects. The present study evaluated the discriminative stimulus effects of a speedball combination of cocaine and heroin. Three rhesus monkeys were trained to discriminate vehicle from a 10:1 ratio of cocaine (0.4 mg/kg) in combination with heroin (0.04 mg/kg). Both cocaine alone and heroin alone substituted completely for the cocaine/heroin combination, although cocaine and heroin were more potent when administered together than when administered alone. Combined pretreatment with the dopamine antagonist flupenthixol and the opioid antagonist quadazocine dose-dependently antagonized the discriminative stimulus effects of the cocaine/heroin combination, but pretreatment with either antagonist alone was less effective. These findings suggest that either cocaine or heroin alone was sufficient to substitute for the cocaine/heroin training combination. To characterize the discriminative stimulus properties of this speedball more fully, a series of cocaine-like and heroin-like agonists were studied in substitution tests. The indirect dopamine agonists CFT, amphetamine and bupropion and the mu opioid agonists alfentanil, fentanyl and morphine produced high levels of speedball-appropriate responding. However, the indirect dopamine agonist GBR12909, the D1 dopamine agonist SKF82958, the D2 dopamine agonist quinpirole and the partial mu opioid agonist nalbuphine did not substitute for the cocaine/heroin combination. Because these compounds produce discriminative stimulus effects similar to either cocaine or mu opioid agonists alone, these findings suggest that the discriminative stimulus effects of the cocaine/heroin combination do not overlap completely with the effects of cocaine and heroin alone. Finally, a series of compounds that produce partial or no substitution for cocaine or mu agonists alone also did not substitute for the cocaine/heroin combination, which indicates that the discriminative stimulus effects of the combination were pharmacologically selective. Taken together, these findings suggest that a combination of cocaine and heroin produces a pharmacologically selective discriminative stimulus complex that includes aspects of both component drugs.

Publication types

  • Comparative Study
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Animals
  • Azocines / pharmacology
  • Behavior, Animal / drug effects
  • Cocaine / pharmacology*
  • Discrimination Learning / drug effects*
  • Dopamine Agonists / pharmacology
  • Dopamine Antagonists / pharmacology
  • Dose-Response Relationship, Drug
  • Drug Combinations
  • Flupenthixol / pharmacology
  • Heroin / pharmacology*
  • Macaca mulatta
  • Male
  • Narcotic Antagonists / pharmacology
  • Receptors, Opioid, mu / agonists
  • Receptors, Opioid, mu / metabolism


  • Azocines
  • Dopamine Agonists
  • Dopamine Antagonists
  • Drug Combinations
  • Narcotic Antagonists
  • Receptors, Opioid, mu
  • Heroin
  • Flupenthixol
  • Cocaine
  • quadazocine