Stereochemistry of mephedrone neuropharmacology: enantiomer‐specific behavioural and neurochemical effects in rats
Ryan A. Gregg, Michael H. Baumann, John S. Partilla, Julie S. Bonano, Alexandre G. Vouga, Christopher S. Tallarida, Venkata Velvadapu, Garry R. Smith, M. Melissa Peet, Allen B. Reitz, S. Stevens Negus, Scott M. Rawls
British Journal of Pharmacology September 26, 2014 DOI: 10.1111/bph.12951 (opens in new tab)
Study at a glance
AI-extracted from the abstract| Characteristics | Experimental study Peer reviewed |
|---|---|
| Population | Rat brain synaptosomes and live rats |
| Interventions | R-mephedrone S-mephedrone |
| Keywords | Pharmacology Enantiomer Neurochemical Stereochemistry |
| Citations | 79 |
| Key findings | R-MEPH produced greater repetitive movements, sensitization, and reward than S-MEPH, likely due to its weaker serotonergic activity. |
Abstract
Background: AND
Purpose: Synthetic cathinones, commonly referred to as 'bath salts', are a group of amphetamine-like drugs gaining popularity worldwide. 4-Methylmethcathinone (mephedrone, MEPH) is the most commonly abused synthetic cathinone in the UK, and exerts its effects by acting as a substrate-type releaser at monoamine transporters. Similar to other cathinone-related compounds, MEPH has a chiral centre and exists stably as two enantiomers: R-mephedrone (R-MEPH) and S-mephedrone (S-MEPH). EXPERIMENTAL APPROACH: Here, we provide the first investigation into the neurochemical and behavioural effects of R-MEPH and S-MEPH. We analysed both enantiomers in rat brain synaptosome neurotransmitter release assays and also investigated their effects on locomotor activity (e.g. ambulatory activity and repetitive movements), behavioural sensitization and reward. KEY
Results: Both enantiomers displayed similar potency as substrates (i.e. releasers) at dopamine transporters, but R-MEPH was much less potent than S-MEPH as a substrate at 5-HT transporters. Locomotor activity was evaluated in acute and repeated administration paradigms, with R-MEPH producing greater repetitive movements than S-MEPH across multiple doses. After repeated drug exposure, only R-MEPH produced sensitization of repetitive movements. R-MEPH produced a conditioned place preference whereas S-MEPH did not. Lastly, R-MEPH and S-MEPH produced biphasic profiles in an assay of intracranial self-stimulation (ICSS), but R-MEPH produced greater ICSS facilitation than S-MEPH.
Conclusions: AND
Implications: Our data are the first to demonstrate stereospecific effects of MEPH enantiomers and suggest that the predominant dopaminergic actions of R-MEPH (i.e. the lack of serotonergic actions) render this stereoisomer more stimulant-like when compared with S-MEPH. This hypothesis warrants further study.