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.

Keywords: 4-Methylcathinone; Cathinone; Drug abuse; Intracranial self-stimulation; Rat; Stereoselectivity.

Figure 1

Chemical structures of S(−) and R(+) enantiomers of cathinone and 4-methylcathinone tested in this study.

Figure 2

Effects of (a, b) cathinone and (c, d) 4-methylcathinone enantiomers on monoamine release via DAT, SERT, and NET in rat brain tissue. Abscissae: drug concentration in M. Ordinates: percent maximal monoamine release. Each point shows mean±SD for n=3 experiments performed in triplicate. EC₅₀ values derived from the concentration–effect curves are shown in Table 1.

Figure 3

Effects of cathinone enantiomers on ICSS. (a, b) Abscissae: frequency of electrical brain stimulation in log Hz. Ordinates: rate of ICSS maintained by each frequency of brain stimulation, expressed as percent maximum control rate (%MCR). (c, d) Abscissae: drug dose in mg/kg. Ordinates: rate of ICSS maintained across all brain stimulation frequencies, expressed as percent baseline number of stimulations per component. Filled points in (a) and (b) represent frequencies at which ICSS rates were statistically different from vehicle rates (P<0.05). In (c) and (d) * indicate significant increases and ^# indicated significant decreases in ICSS rates relative to vehicle for at least one stimulation frequency as determined by analysis of frequency–rate curves in panels (a) and (b). All data show mean±SEM for n=6 rats.

Figure 4

Effects of 4-methylcathinone enantiomers on ICSS. (a, b) Abscissae: frequency of electrical brain stimulation in log Hz. Ordinates: rate of ICSS maintained by each frequency of brain stimulation, expressed as percent maximum control rate (%MCR). (c, d) Abscissae: drug dose in mg/kg. Ordinates: rate of ICSS maintained across all brain stimulation frequencies, expressed as percent baseline number of stimulations per component. Filled points in (a) and (b) represent frequencies at which ICSS rates were statistically different from vehicle rates (P<0.05). In (c) and (d) * indicate significant increases and ^# indicated significant decreases in ICSS rates relative to vehicle for at least one stimulation frequency as determined by analysis of frequency–rate curves in panels (a) and (b). All data show mean±SEM for n=6 rats.