title: Comparative neuropharmacology of three psychostimulant cathinone derivatives: butylone, mephedrone and methylone.
abstract: OBJECTIVE
  Here, we have compared the neurochemical profile of three new cathinones, butylone, mephedrone and methylone, in terms of their potential to inhibit plasmalemmal and vesicular monoamine transporters. Their interaction with 5-HT and dopamine receptors and their psychostimulant effect was also studied.
  
  
  METHODS
  Locomotor activity was recorded in mice following different doses of cathinones. Monoamine uptake assays were performed in purified rat synaptosomes. Radioligand-binding assays were carried out to assess the affinity of these compounds for monoamine transporters or receptors.
  
  
  RESULTS
  Butylone, mephedrone and methylone (5-25 mg·kg(-1) ) caused hyperlocomotion, which was prevented with ketanserin or haloperidol. Methylone was the most potent compound inhibiting both [(3) H]5-HT and [(3) H]dopamine uptake with IC(50) values that correlate with its affinity for dopamine and 5-HT transporter. Mephedrone was found to be the cathinone derivative with highest affinity for vesicular monoamine transporter-2 causing the inhibition of dopamine uptake. The affinity of cathinones for 5-HT(2A) receptors was similar to that of MDMA.
  
  
  CONCLUSIONS
  Butylone and methylone induced hyperlocomotion through activating 5-HT(2A) receptors and increasing extra-cellular dopamine. They inhibited 5-HT and dopamine uptake by competing with substrate. Methylone was the most potent 5-HT and dopamine uptake inhibitor and its effect partly persisted after withdrawal. Mephedrone-induced hyperlocomotion was dependent on endogenous 5-HT. Vesicular content played a key role in the effect of mephedrone, especially for 5-HT uptake inhibition. The potency of mephedrone in inhibiting noradrenaline uptake suggests a sympathetic effect of this cathinone.
authors.affiliation: Department of Pharmacology and Therapeutic Chemistry (Pharmacology Section) and Institute of Biomedicine (IBUB), University of Barcelona, Barcelona, Spain.
authors.forename: Raul
authors.initials: R
authors.lastname: López-Arnau
authors.forename: Jose
authors.initials: J
authors.lastname: Martínez-Clemente
authors.forename: David
authors.initials: D
authors.lastname: Pubill
authors.forename: Elena
authors.initials: E
authors.lastname: Escubedo
authors.forename: Jorge
authors.initials: J
authors.lastname: Camarasa
mesh_terms: D015104:3,4-Methylenedioxyamphetamine / Q000031:analogs & derivatives* / Q000737:chemistry / Q000494:pharmacology; D000818:Animals; D001921:Brain / Q000187:drug effects / Q000378:metabolism; D002352:Carrier Proteins; D000697:Central Nervous System Stimulants / Q000737:chemistry / Q000494:pharmacology; D004298:Dopamine / Q000378:metabolism; D018492:Dopamine Antagonists / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D006220:Haloperidol / Q000494:pharmacology; D007650:Ketanserin / Q000494:pharmacology; D008297:Male; D008694:Methamphetamine / Q000031:analogs & derivatives* / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology; D051379:Mice; D015394:Molecular Structure; D009043:Motor Activity / Q000187:drug effects*; D009638:Norepinephrine / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D012701:Serotonin / Q000378:metabolism; D012702:Serotonin Antagonists / Q000494:pharmacology; D013574:Synaptosomes / Q000187:drug effects
chemical_list: D002352:Carrier Proteins; D000697:Central Nervous System Stimulants; D018492:Dopamine Antagonists; D012702:Serotonin Antagonists; D012701:Serotonin; D008694:Methamphetamine; D015104:3,4-Methylenedioxyamphetamine; C548233:mephedrone; D007650:Ketanserin; D006220:Haloperidol; C400939:methylone; D004298:Dopamine; D009638:Norepinephrine; C544130:2-methylamino-1-(3,4-methylenedioxyphenyl)butan-1-one