Stereochemistry of mephedrone neuropharmacology: enantiomer‐specific behavioural and neurochemical effects in rats

Abstract

BACKGROUND AND PURPOSESynthetic 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 APPROACHHere, 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 RESULTSBoth 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 IMPLICATIONSOur 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. Abbreviations

Synthetic cathinone MDPV downregulates glutamate transporter subtype I (GLT-1) and produces rewarding and locomotor-activating effects that are reduced by a GLT-1 activator

“…This finding parallels our published findings with mephedrone (Gregg et al, 2014), which acts as a monoamine transporter substrate compared to MDPV that functions as a transporter blocker (Baumann et al, 2013). In the present experiments, pretreatment with CTX prior to varying acute doses of MDPV did not affect MDPV-induced increases in total repetitive movements or ambulatory activity.…”

“…This paradigm was adapted from a behavioral sensitization paradigm we employed with cocaine and the synthetic cathinone mephedrone (Gregg et al, 2014; Gregg et al, 2013a, Gregg et al, 2013b; Kalivas and Duffy, 1998). Rats that were housed together did not receive the same treatment, but instead, always comprised one rat receiving MDPV and another receiving saline, which were paired for their dissection time.…”

“…Basal locomotor activity was recorded for at least 30 min prior to the first injection in both acute and repeated dosing paradigms, followed by recording of locomotor activity for 90 min after saline or MDPV injection. Activity was recorded using a Digiscan DMicro System (Accuscan, Inc., Columbus, OH) (Gregg et al, 2013a; Gregg et al, 2013b; Gregg et al, 2014). Activity chambers consisted of transparent plastic boxes (45 cm (L) × 20 cm (W) × 20 cm (H)) set inside metal frames equipped with 16 infrared light emitters and detectors spaced 2.5 cm apart.…”

“…CPP experiments (N = 8–12 per group) were conducted in experimentally naïve rats using a 4-day biased design (Gregg et al, 2014). CPP chambers consisted of two compartments (each 45 cm (L) × 20 cm (W) × 20 cm (H)) separated by a removable door.…”

Chiral and stable isotope analysis of synthetic cathinones

“…On the other hand, depending on the actual synthetic cathinone, different enantioselective pharmacodynamics has been observed. While S-(−)-cathinone and S-(−)-methcathinone are about three-fold more potent than their R forms [12,13], R-(+)-4-methylmethcathinone has stronger dopaminergic stimulating effects that S-(−)-4-methylmethcathinone [14]. Therefore, chiral analysis of synthetic cathinones is also important in toxicological and pharmacological studies.…”