Contribution of monoaminergic mechanisms to the discriminative stimulus effects of 3,4-methylenedioxypyrovalerone (MDPV) in Sprague-Dawley rats
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3,4-Methylenedioxypyrovalerone (MDPV) is a popular synthetic cathinone reported to have a high abuse potential. Recent preclinical research indicates the psychopharmacology of MDPV is comparable to cocaine. Despite a recent influx of research on the psychopharmacology of MDPV, few studies have employed preclinical drug discrimination methods to discern the neurochemical mechanisms involved in its interoceptive stimulus effects.
The aim of this study was to evaluate a variety of monoaminergic agents for substitution, potentiation, or antagonism in rats trained to discriminate MDPV.
Male Sprague-Dawley rats were trained to discriminate 0.5 (experiment 1) or 1 mg/kg MDPV (experiment 2) from saline under an FR 20 schedule of food reinforcement. In experiment 1, MDMA, MDA, and their respective optical isomers (0.75–3 mg/kg), cocaine (2.5–20 mg/kg), GBR 12909 (5–40 mg/kg), and desipramine (3.2–10 mg/kg) were assessed for substitution. GBR 12909 (40 mg/kg) and desipramine (3.2 mg/kg) were subsequently assessed for potentiation of the MDPV cue. In experiment 2, stimulus antagonism tests were conducted with dopamine antagonists (Sch 23390, haloperidol) and serotonin antagonists (pirenperone, MDL100907, WAY 100635).
The MDMA and MDA enantiomers produced divergent results, with virtually no substitution by (−)-MDMA or (−)-MDA, partial substitution with (+)-MDA, and full substitution with (+)-MDMA, as well as full substitution by the racemates, (±)-MDMA and (±)-MDA. Consistent with previous findings, cocaine fully substituted for MDPV. Although no dose of GBR 12909 or desipramine substituted for MDPV, these reuptake inhibitors enhanced the discriminative stimulus effects of lower MDPV doses. Both D1 (Sch 23390) and D2 (haloperidol) DA antagonists attenuated 1 mg/kg MDPV discrimination, whereas none of the 5-HT antagonists assessed altered MDPV discrimination.
These findings indicate MDPV’s interoceptive stimulus effects are mediated predominantly by dopaminergic actions, although serotonergic and/or noradrenergic modulation of these effects cannot be ruled out. Further investigations into the neurochemical actions involved in the discriminative stimulus effects of MDPV may serve to inform medication discovery and development for the treatment of MDPV abuse.
Keywords3,4-Methylenedioxypyrovalerone Sprague-Dawley rats Synthetic cathinones Drug discrimination Dopamine
This research was supported by a grant from the National Institutes of Health (R15 DA038295). The National Institute on Drug Abuse Drug Control Supply Program and the National Institutes of Mental Health Chemical Synthesis and Drug Supply Program provided several of the drugs used in this study. A portion of this work (GBR 12909) was supported by the intramural research programs of the National Institute on Drug Abuse and the National Institute on Alcohol Abuse and Alcoholism.
Compliance with ethical standards
All procedures were reviewed and approved by the Western Michigan University Institutional Animal Care and Use Committee, and were in accordance with the guidelines of the Guide for the Care and Use of Laboratory Animals (National Research Council of the National Academies 2011).
Conflict of interest
The authors declare that they have no conflict of interest.
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