Increased side-chain length confers a greater dopaminergic phenotype and increased reinforcing efficacy to cathinone analogs of MDMA

In recent years, synthetic cathinone compounds have been utilized in “Ecstasy” formulations in lieu of MDMA, some of which are congeners of MDMA. The current study aimed to assess structure-activity relations of the discriminative stimulus and reinforcing effects among three synthetic cathinone analogs of MDMA: methylone, butylone, and pentylone. Rats were trained to discriminate methamphetamine from vehicle. Dose-response studies were performed with each of the test compounds and the lowest substituting dose was then tested in the presence of a range of doses of the D1-selective antagonist SCH23390. A separate group of rats was trained to self-administer methamphetamine under a FR10 schedule of reinforcement. Rats then self-administered methamphetamine, MDMA, and the test compounds under a progressive ratio schedule of reinforcement. Each of the test compounds fully substituted for the discriminative stimulus effects of methamphetamine. SCH23390 fully and dose-dependently antagonized the methamphetamine-appropriate responding produced by these compounds with methylone being the most sensitive to the effects of SCH23390, followed by butylone, then pentylone. In the self-administration studies, breakpoints increased concurrently with side-chain length. Methylone’s breakpoint was higher than saline, but the same as MDMA. The breakpoints for butylone and pentylone were both greater than saline or MDMA, but only pentylone produced responding comparable to methamphetamine. These data indicate that as side-chain length increases, the sensitivity to SCH23390 decreases and self-administration increases, suggesting that side-chain length is positively associated with dopaminergic phenotype and reinforcing efficacy. Furthermore, these synthetic cathinones may drive compulsive use of “Ecstasy” given their presence in “Ecstasy” formulations and increased reinforcing efficacy relative to MDMA.