Abuse-Related Neurochemical Effects of Para-Substituted Methcathinone Analogs in Rats: Microdialysis Studies of Nucleus Accumbens Dopamine and Serotonin

Abstract

Methcathinone (MCAT) is a monoamine releaser and parent compound to a new class of designer drugs that includes the synthetic cathinones mephedrone and flephedrone. Using MCAT and a series of para-substituted (or 4-substituted) MCAT analogs, it has been previously shown that expression of abuserelated behavioral effects in rats correlates both with the volume of the para substituent and in vitro neurochemical selectivity to promote monoamine release via the dopamine (DA) versus serotonin (5-HT) transporters in rat brain synaptosomes. The present study used in vivo microdialysis to determine the relationship between these previous measures and the in vivo neurochemical selectivity of these compounds to alter nucleus accumbens (NAc) DA and 5-HT levels. Male Sprague-Dawley rats were implanted with bilateral guide cannulae targeting the NAc. MCAT and five para-substituted analogs (4-F, 4-Cl, 4-Br, 4-CH 3, and 4-OCH 3 ) produced dose-and time-dependent increases in NAc DA and/or 5-HT levels. Selectivity was determined as the dose required to increase peak 5-HT levels by 250% divided by the dose required to increase peak DA levels by 250%. This measure of in vivo neurochemical selectivity varied across compounds and correlated with 1) in vivo expression of abuse-related behavioral effects (r 5 0.89, P 5 0.02); 2) in vitro selectivity to promote monoamine release via DA and 5-HT transporters (r 5 0.95, P , 0.01); and 3) molecular volume of the para substituent (r 5 20.85, P 5 0.03). These results support a relationship between these molecular, neurochemical, and behavioral measures and support a role for molecular structure as a determinant of abuse-related neurochemical and behavioral effects of MCAT analogs.

Structure-Activity Relationships of Substituted Cathinones, with Transporter Binding, Uptake, and Release

“…These results are consistent with para halide MCAT substitutions decreasing the DAT:SERT release potencies from rat synaptosomes (Bonano et al, 2015). MCAT robustly increases extracellular DA, whereas 4-F MCAT and 4-Cl MCAT robustly and 4-Br MCAT modestly increase both extracellular DA and 5-HT, as measured by microdialysis in rats (Suyama et al, 2016). The ratios of (in vivo) potencies to release DA and 5-HT correlate positively with maximal ICSS, a procedure that evaluates abuse potential, and negatively with the steric bulk of the compounds (Suyama et al, 2016).…”

“…MCAT robustly increases extracellular DA, whereas 4-F MCAT and 4-Cl MCAT robustly and 4-Br MCAT modestly increase both extracellular DA and 5-HT, as measured by microdialysis in rats (Suyama et al, 2016). The ratios of (in vivo) potencies to release DA and 5-HT correlate positively with maximal ICSS, a procedure that evaluates abuse potential, and negatively with the steric bulk of the compounds (Suyama et al, 2016). Thus, the abuse potential may decrease, whereas more MDMA-like empathogenic activity may increase, within this series.…”

“…MDAI, an indane analog of MDMA first synthesized in 1990, substitutes for MDMA and cocaine in drug discrimination assays and produces conditioned place preference (Nichols et al, 1990;Oberlender and Nichols, 1991;Gatch et al, 2016). In rats, intraperitoneal injections of 4-chloromethcathinone (4-Cl MCAT) and 4-bromomethcathinone (4-Br MCAT) produce increases in nucleus accumbens extracellular dopamine (DA) and serotonin [5-hydroxy-tryptamine (5-HT)] levels (Suyama et al, 2016) but cause minimal effects on intracranial self-stimulation (ICSS), whereas both 4-MEC and a-PVP affect ICSS similar to METH (Watterson et al, 2014). Rats self-administer a-PVP (Aarde et al, 2015).…”

Cocaine-like discriminative stimulus effects of amphetamine, cathinone, methamphetamine, and their 3,4-methylenedioxy analogs in male rhesus monkeys

“…However, there are a paucity of in vivo studies that have determined the behavioral consequences of different chemical structure modifications to cathinone. Furthermore, most studies have focused on phenyl ring modifications to N -methylcathinone (methcathinone) (Bonano et al 2015; Sakloth et al 2015; Suyama et al 2016), given these analogs have been most prevalent in Drug Enforcement Administration seizures and forensic toxicology reports (DEA 2014). Moreover, only one study has examined the effects of a 3,4-methylenedixoy moiety addition to cathinone (3,4-methylenedioxycathinone; MDC) in rats (Dal Cason et al 1997).…”

Assessing the role of dopamine in the differential neurotoxicity patterns of methamphetamine, mephedrone, methcathinone and 4-methylmethamphetamine

“…Users of the drug report subjective effects including feelings of euphoria, well-being, and altered sensory perceptions, but acute toxicity and occasional deaths have also been reported (Papaseit et al, 2016). MEPH has a markedly similar neurotransmitter releasing effect on dopamine (DA) and serotonin (5-HT), mediated by their respective reuptake transporters, in comparison with methamphetamine (METH), its non-β-keto analog (Baumann et al, 2012; Cameron et al, 2013; Eshleman et al, 2013; Golembiowska et al, 2016; Lopez-Arnau et al, 2012; Simmler et al, 2013; Suyama et al, 2016). Additionally, MEPH shares similarities with METH in its acute effects on thermoregulation (Baumann et al, 2012; Martinez-Clemente et al, 2014; Shortall et al, 2016), locomotor stimulation (Baumann et al, 2012; Lopez-Arnau et al, 2012; Marusich et al, 2012; Motbey et al, 2012; Nguyen et al, 2016; Wright et al, 2012), and indicators of addictive liability (Creehan et al, 2015; Hadlock et al, 2011; Karlsson et al, 2014; Lisek et al, 2012).…”