Effects of cocaine on the discriminative stimulus and reinforcing effects of mephedrone in male rats

Abstract

Rationale: Abuse of cathinones has been a worldwide health concern for some time. Their chemical structures and wide variation in pharmacodynamic effects have led to clinical and preclinical effects that can be both similar to and different from other psychoactive substances such as methylenedioxymethamphetamine (MDMA), methamphetamine, and cocaine.

Objective: The present study examined the discriminative stimulus and reinforcing effects of mephedrone to further characterize the behavioral and pharmacological profile of this first-generation substituted methcathinone.

Methods: Rats were trained to discriminate mephedrone (3.2 mg/kg) from saline under a fixed-ratio 20 (FR-20) schedule of food presentation. After establishing dose-effect curves for increasing cumulative doses of mephedrone, substitution tests were conducted with bupropion (5.6-32 mg/kg), cocaine (1.8-18 mg/kg), morphine (0.56-10 mg/kg), and amitriptyline (3.2-32 mg/kg). In addition, cocaine (3.2-18 mg/kg) and the serotonin type-2 (5-HT2) receptor antagonist ritanserin (1, 3.2, and 10 mg/kg) were administered prior to the cumulative doses of mephedrone. Lastly, varying infusion doses of cocaine were substituted for mephedrone in subjects trained to self-administer mephedrone, and varying infusion doses of mephedrone were substituted for cocaine in subjects trained to self-administer cocaine to assess the importance of drug history on the reinforcing effects of mephedrone.

Results: Of the drugs tested, cocaine had the highest level of mephedrone-lever responding when administered alone (73.5%). In combination with mephedrone, cocaine shifted the mephedrone dose-effect curve upwards in an infra-additive manner. Ritanserin had a small, but non-significant, effect on mephedrone's discriminative stimulus effects. An extensive history (baseline) of cocaine self-administration increased mephedrone self-administration compared to that obtained in mephedrone-trained subjects, whereas a baseline of mephedrone self-administration decreased cocaine self-administration compared to that obtained in cocaine-trained subjects.

Conclusion: The similarity between the discriminative stimulus effects of cocaine and mephedrone in male rats suggests an important overlap and the relative importance of the dopamine (DAT) and serotonin (SERT) transporters. The self-administration data suggest that mephedrone is less reinforcing than cocaine, but that a history of responding for cocaine can increase the reinforcing effects of mephedrone.

Keywords: Bupropion; Cocaine; Drug discrimination; Drug history; Mephedrone; Rats; Self-administration; Synthetic cathinone.