title: Abuse-related neurochemical and behavioral effects of cathinone and 4-methylcathinone stereoisomers in rats.
abstract: Cathinone and many of its analogs produce behavioral effects by promoting transporter-mediated release of the monoamine neurotransmitters dopamine, norepinephrine and/or serotonin. Stereoselectivity is one determinant of neurochemical and behavioral effects of cathinone analogs. This study compared effectiveness of the S(-) and R(+) enantiomers of cathinone and 4-methylcathinone to produce in vitro monoamine release and in vivo abuse-related behavioral effects in rats. For neurochemical studies, drug effects were evaluated on monoamine release through dopamine, norepinephrine, and serotonin transporters (DAT, NET and SERT, respectively) in rat brain synaptosomes. For behavioral studies, drug effects were evaluated on responding for electrical brain stimulation in an intracranial self-stimulation (ICSS) procedure. The cathinone enantiomers differed in potency [S(-)>R(+)], but both enantiomers were >50-fold selective at promoting monoamine release through DAT vs. SERT, and both enantiomers produced ICSS facilitation. The 4-methylcathinone enantiomers also differed in potency [S(-)>R(+)]; however, in neurochemical studies, the decrease in potency from S(-) to R(+)4-methylcathinone was less for DAT than for SERT, and as a result, DAT vs. SERT selectivity was greater for R(+) than for S(-)4-methylcathinone (4.1- vs. 1.2-fold). Moreover, in behavioral studies, S(-)4-methylcathinone produced only ICSS depression, whereas R(+)4-methylcathinone produced ICSS facilitation. This study provides further evidence for stereoselectivity in neurochemical and behavioral actions of cathinone analogs. More importantly, stereoselective 4-methylcathinone effects on ICSS illustrate the potential for diametrically opposite effects of enantiomers in a preclinical behavioral assay of abuse potential.
authors.affiliation: Department of Pharmacology and Toxicology, Virginia Commonwealth University, 410 N. 12th St., PO Box 980613, Richmond, VA 23298, USA.
authors.forename: Blake A
authors.initials: BA
authors.lastname: Hutsell
authors.affiliation: Designer Drug Research Unit, Intramural Research Program, National Institute on Drug Abuse, National Institutes of Health, Baltimore, MD, USA.
authors.forename: Michael H
authors.initials: MH
authors.lastname: Baumann
authors.affiliation: Designer Drug Research Unit, Intramural Research Program, National Institute on Drug Abuse, National Institutes of Health, Baltimore, MD, USA.
authors.forename: John S
authors.initials: JS
authors.lastname: Partilla
authors.affiliation: Department of Pharmacology and Toxicology, Virginia Commonwealth University, 410 N. 12th St., PO Box 980613, Richmond, VA 23298, USA; Institute for Drug and Alcohol Studies, Virginia Commonwealth University, USA.
authors.forename: Matthew L
authors.initials: ML
authors.lastname: Banks
authors.affiliation: Department of Medicinal Chemistry, Virginia Commonwealth University, Richmond, VA, USA.
authors.forename: Rakesh
authors.initials: R
authors.lastname: Vekariya
authors.affiliation: Department of Medicinal Chemistry, Virginia Commonwealth University, Richmond, VA, USA.
authors.forename: Richard A
authors.initials: RA
authors.lastname: Glennon
authors.affiliation: Department of Pharmacology and Toxicology, Virginia Commonwealth University, 410 N. 12th St., PO Box 980613, Richmond, VA 23298, USA; Institute for Drug and Alcohol Studies, Virginia Commonwealth University, USA. Electronic address: ssnegus@vcu.edu.
authors.forename: S Stevens
authors.initials: SS
authors.lastname: Negus
mesh_terms: D000470:Alkaloids / Q000009:adverse effects* / Q000737:chemistry*; D000704:Analysis of Variance; D000818:Animals; D000697:Central Nervous System Stimulants / Q000009:adverse effects* / Q000737:chemistry; D004195:Disease Models, Animal; D050483:Dopamine Plasma Membrane Transport Proteins / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D066298:In Vitro Techniques; D008297:Male; D051381:Rats; D017207:Rats, Sprague-Dawley; D012653:Self Stimulation; D050486:Serotonin Plasma Membrane Transport Proteins / Q000378:metabolism; D013237:Stereoisomerism; D019966:Substance-Related Disorders / Q000378:metabolism* / Q000503:physiopathology*
chemical_list: D000470:Alkaloids; D000697:Central Nervous System Stimulants; D050483:Dopamine Plasma Membrane Transport Proteins; D050486:Serotonin Plasma Membrane Transport Proteins; C023665:cathinone; C000612305:4-methylcathinone
keywords: 4-Methylcathinone; Cathinone; Drug abuse; Intracranial self-stimulation; Rat; Stereoselectivity