Interactions between reinforcement history and drug-primed reinstatement: Studies with MDPV and mixtures of MDPV and caffeine

Michelle R. Doyle, Agnieszka Sulima, Kenner C. Rice, Gregory T. Collins

Research output: Contribution to journalArticlepeer-review

7 Scopus citations


Many drugs of abuse are mixed with other psychoactive substances (e.g., caffeine) prior to their sale or use. Synthetic cathinones (e.g., 3,4-methylenedioxypyrovalerone [MDPV]) are commonly mixed with caffeine or other cathinones (e.g., 3,4-methylenedioxy-N-methylcathinone [methylone]), and these “bath salts” mixtures (e.g., MDPV + caffeine) can exhibit supra-additive interactions with regard to their reinforcing and discriminative stimulus properties. However, little is known about relapse-related effects of drug mixtures. In these studies, male Sprague–Dawley rats self-administered 0.032 mg/kg/inf MDPV or a mixture of MDPV + caffeine (0.029 + 0.66 mg/kg/inf, respectively) and then underwent multiple rounds of extinction and reinstatement testing to evaluate the influence of reinforcement history and drug-associated stimuli on the effectiveness of saline (drug-paired stimuli alone), MDPV (0.032–1.0 mg/kg), caffeine (1.0–32 mg/kg), and mixtures of MDPV:caffeine (in 3:1, 1:1, and 1:3 ratios, relative to each drug's ED50) to reinstate responding. Dose-addition analyses were used to determine the nature of the drug–drug interaction for each mixture. MDPV and caffeine dose-dependently reinstated responding and were equally effective, regardless of reinforcement history. Most fixed ratio mixtures of MDPV + caffeine exhibited supra-additive interactions, reinstating responding to levels greater than was observed with caffeine and/or MDPV alone. Drug-associated stimuli also played a key role in reinstating responding, especially for caffeine. Together, these results demonstrate that the composition of drug mixtures can impact relapse-related effects of drug mixtures, and “bath salts” mixtures (MDPV + caffeine) may be more effective at promoting relapse-related behaviors than the constituents alone. Further research is needed to determine how other polysubstance reinforcement histories can impact relapse-related behaviors.

Original languageEnglish (US)
Article numbere12904
JournalAddiction Biology
Issue number2
StatePublished - Mar 2021


  • MDPV
  • bath salts
  • caffeine
  • drug mixtures
  • reinstatement

ASJC Scopus subject areas

  • Medicine (miscellaneous)
  • Pharmacology
  • Psychiatry and Mental health


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