title: Cocaine-like discriminative stimulus effects of alpha-pyrrolidinovalerophenone, methcathinone and their 3,4-methylenedioxy or 4-methyl analogs in rhesus monkeys.
abstract: Synthetic cathinones are beta-ketone amphetamine analogs that have emerged as a heterogeneous class of abused compounds that function as either monoamine transporter substrates or inhibitors. Pre-clinical drug discrimination procedures are useful for interrogating structure-activity relationships of abuse-related drug effects; however, in vivo structure-activity relationship comparisons between synthetic cathinones with different mechanisms of action are lacking. The aim of the present study was to determine whether the cocaine-like discriminative stimulus effects of the monoamine transporter inhibitor alpha-pyrrolidinovalerophenone (alpha-PVP) and the monoamine transporter substrate methcathinone were differentially sensitive to 3,4-methylenedioxy and 4-methyl substitutions. Male rhesus monkeys (n = 4) were trained to discriminate intramuscular cocaine (0.32 mg/kg) from saline in a two-key food-reinforced discrimination procedure. Potency and timecourse of cocaine-like discriminative stimulus effects were determined for (±)-alpha-PVP, (±)-methcathinone and their 3,4-methylenedioxy or 4-methyl analogs. Alpha-PVP and methcathinone produced dose- and time-dependent cocaine-like effects. A 3,4-methylenedioxy addition to either alpha-PVP or methcathinone (methylone) did not alter the potency or efficacy to produce cocaine-like effects, but did prolong the time course. A 4-methyl addition to alpha-PVP (pyrovalerone) did not alter the potency or efficacy to produce cocaine-like effects, but did prolong the time course. In contrast, addition of a 4-methyl moiety to methcathinone (4MMC; mephedrone) significantly attenuated efficacy to produce cocaine-like effects. Overall, these results suggest different structural requirements for cocaine-like discriminative stimulus effects of monoamine transporter inhibitor and substrate synthetic cathinone analogs. Given that 4MMC is more hydrophobic than MDMC, these results suggest that hydrophobicity may be an important determinant for limiting monoamine transporter substrate abuse-related behavioral effects.
authors.affiliation: Department of Pharmacology and Toxicology, Virginia Commonwealth University, Richmond, VA, USA, 23298.
authors.forename: Douglas A
authors.initials: DA
authors.lastname: Smith
authors.affiliation: Department of Pharmacology and Toxicology, Virginia Commonwealth University, Richmond, VA, USA, 23298.|Institute for Drug and Alcohol Studies, Virginia Commonwealth University, Richmond, VA, USA, 23298.
authors.forename: S Stevens
authors.initials: SS
authors.lastname: Negus
authors.affiliation: Department of Pharmacology and Toxicology, Virginia Commonwealth University, Richmond, VA, USA, 23298.
authors.forename: Justin L
authors.initials: JL
authors.lastname: Poklis
authors.affiliation: Center for Drug Discovery, Research Triangle Institute, Research Triangle Park, NC, USA, 27709.
authors.forename: Bruce E
authors.initials: BE
authors.lastname: Blough
authors.affiliation: Department of Pharmacology and Toxicology, Virginia Commonwealth University, Richmond, VA, USA, 23298.|Institute for Drug and Alcohol Studies, Virginia Commonwealth University, Richmond, VA, USA, 23298.
authors.forename: Matthew L
authors.identifier: http://orcid.org/0000-0003-4949-5246
authors.initials: ML
authors.lastname: Banks
mesh_terms: D000818:Animals; D000697:Central Nervous System Stimulants; D003042:Cocaine; D003216:Conditioning, Operant; D004193:Discrimination Learning / Q000502:physiology*; D018765:Dopamine Uptake Inhibitors; D007273:Injections, Intramuscular; D008253:Macaca mulatta; D008297:Male; D008694:Methamphetamine / Q000031:analogs & derivatives*; D011427:Propiophenones; D011759:Pyrrolidines; D012054:Reinforcement, Psychology
chemical_list: D000697:Central Nervous System Stimulants; D018765:Dopamine Uptake Inhibitors; D011427:Propiophenones; D011759:Pyrrolidines; C542924:alpha-pyrrolidinovalerophenone; C047806:monomethylpropion; D008694:Methamphetamine; C548233:mephedrone; D003042:Cocaine; C400939:methylone; C005719:pyrovalerone
keywords: Alpha-PVP; discrimination; non-human primates