Hutsell Blake A, Baumann Michael H, Partilla John S, Banks Matthew L, Vekariya Rakesh, Glennon Richard A, Negus S Stevens
Department of Pharmacology and Toxicology, Virginia Commonwealth University, 410 N. 12th St., PO Box 980613, Richmond, VA 23298, USA.
Designer Drug Research Unit, Intramural Research Program, National Institute on Drug Abuse, National Institutes of Health, Baltimore, MD, USA.
Eur Neuropsychopharmacol. 2016 Feb;26(2):288-297. doi: 10.1016/j.euroneuro.2015.12.010. Epub 2015 Dec 11.
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.
卡西酮及其许多类似物通过促进转运体介导的单胺类神经递质多巴胺、去甲肾上腺素和/或5-羟色胺的释放而产生行为效应。立体选择性是卡西酮类似物神经化学和行为效应的一个决定因素。本研究比较了卡西酮和4-甲基卡西酮的S(-)和R(+)对映体在大鼠体内产生体外单胺释放和体内与滥用相关行为效应的有效性。对于神经化学研究，通过大鼠脑突触体中多巴胺、去甲肾上腺素和5-羟色胺转运体（分别为DAT、NET和SERT）评估药物对单胺释放的影响。对于行为研究，在颅内自我刺激（ICSS）程序中，通过对脑电刺激反应来评估药物效应。卡西酮对映体在效力上存在差异[S(-)>R(+)]，但两种对映体在通过DAT促进单胺释放方面比对SERT的选择性均大于50倍，且两种对映体均产生ICSS促进作用。4-甲基卡西酮对映体在效力上也存在差异[S(-)>R(+)]；然而，在神经化学研究中，从S(-)到R(+)4-甲基卡西酮的效力下降对于DAT而言比对SERT要小，因此，R(+)4-甲基卡西酮对DAT与SERT的选择性比对S(-)4-甲基卡西酮更大（4.1倍对1.2倍）。此外，在行为研究中，S(-)4-甲基卡西酮仅产生ICSS抑制，而R(+)4-甲基卡西酮产生ICSS促进作用。本研究为卡西酮类似物神经化学和行为作用中的立体选择性提供了进一步证据。更重要的是，4-甲基卡西酮对ICSS的立体选择性效应说明了对映体在滥用潜力临床前行为试验中可能产生完全相反效应的可能性。
