title: Stereochemistry of mephedrone neuropharmacology: enantiomer-specific behavioural and neurochemical effects in rats.
abstract: OBJECTIVE
  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).
  
  
  METHODS
  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.
  
  
  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
  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.
authors.affiliation: Department of Pharmacology, Temple University School of Medicine, Philadelphia, PA, USA; Center for Substance Abuse Research, Temple University School of Medicine, Philadelphia, PA, USA.
authors.forename: Ryan A
authors.initials: RA
authors.lastname: Gregg
authors.forename: Michael H
authors.initials: MH
authors.lastname: Baumann
authors.forename: John S
authors.initials: JS
authors.lastname: Partilla
authors.forename: Julie S
authors.initials: JS
authors.lastname: Bonano
authors.forename: Alexandre
authors.initials: A
authors.lastname: Vouga
authors.forename: Christopher S
authors.initials: CS
authors.lastname: Tallarida
authors.forename: Venkata
authors.initials: V
authors.lastname: Velvadapu
authors.forename: Garry R
authors.initials: GR
authors.lastname: Smith
authors.forename: M Melissa
authors.initials: MM
authors.lastname: Peet
authors.forename: Allen B
authors.initials: AB
authors.lastname: Reitz
authors.forename: S Stevens
authors.initials: SS
authors.lastname: Negus
authors.forename: Scott M
authors.initials: SM
authors.lastname: Rawls
mesh_terms: D000818:Animals; D001522:Behavior, Animal / Q000187:drug effects*; D001921:Brain / Q000187:drug effects* / Q000378:metabolism; D008297:Male; D008694:Methamphetamine / Q000031:analogs & derivatives* / Q000737:chemistry / Q000494:pharmacology; D009043:Motor Activity / Q000187:drug effects*; D018377:Neurotransmitter Agents / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D013237:Stereoisomerism; D013329:Structure-Activity Relationship
chemical_list: D018377:Neurotransmitter Agents; D008694:Methamphetamine; C548233:mephedrone