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.

Decoding the Structure of Abuse Potential for New Psychoactive Substances: Structure–Activity Relationships for Abuse-Related Effects of 4-Substituted Methcathinone Analogs

“…As a result, the R (+) enantiomer displays a 50-fold greater selectivity than the S (−) enantiomer to promote monoamine release via DAT vs. SERT, and this stereoselectivity in neurochemical effects contributed to stereoselectivity in expression of abuse-related behavioral effects. It is unknown whether this stereoselectivity would also be apparent for other 4-R MCAT analogs, but a similar impact of stereochemistry was observed for isomers of 4-CH 3 cathinone [23]. Importantly, these results suggest that stereoselectivity at the chiral carbon at one end of the 4-R MCAT molecule can influence interactions of the 4-substituent at the other end of the molecule with its own portion of the DAT and SERT substrate-binding pockets.…”

“…The QSAR studies summarized above were conducted with racemic compounds, but more recent studies have identified an additional role for stereoselectivity as a determinant both of 4-R MCAT interactions with transporters and of ultimate expression of abuse-related effects [22, 23]. Specifically, methcathinone, methamphetamine, and many of their analogs possess a single chiral carbon atom (the α carbon signified by the asterisk in Fig.…”

Effects of N-Alkyl-4-Methylamphetamine Optical Isomers on Plasma Membrane Monoamine Transporters and Abuse-Related Behavior

“…Previously established ICSS studies on stereoselectivity of amphetamine and amphetamine-like compounds suggest a difference in isomer potency for compounds that are releasers at monoamine transporters. 33–35 …”

Structure-Activity Relationships of Synthetic Cathinones

“…The abuse-related potential of biogenic amine releasing agents appears to be related to their ability to promote greater release via DAT than via SERT such that DAT-selective agents possess higher abuse liability (see Negus et al, 2007 and Hutsell et al, 2016 for extended discussion). Consistent with this concept is that R (+)mephedrone with 50-fold selectivity for DAT over SERT produced in rats greater locomotor stimulation and rewarding properties as measured by conditioned place preference and facilitation of ICSS than its S (-)enantiomer which produced weak locomotor stimulation and lacked rewarding properties (Gregg et al, 2015).…”

“…Consistent with this concept is that R (+)mephedrone with 50-fold selectivity for DAT over SERT produced in rats greater locomotor stimulation and rewarding properties as measured by conditioned place preference and facilitation of ICSS than its S (-)enantiomer which produced weak locomotor stimulation and lacked rewarding properties (Gregg et al, 2015). For 4-methylcathinone ( 53 ), R (+)53 was less potent than its S -enantiomer to promote release at DAT, but displayed slightly greater DAT versus SERT selectivity and produced abuse-related effects in ICSS (Hutsell et al, 2016). These studies (i.e., those reported by Gregg et al, 2015 and Hutsell et al, 2016) were the first to show the subtle stereochemical relationship between the ability of optical isomers of cathinone analogs to behave as substrates at DAT and SERT and their stimulant or rewarding actions.…”