The Designer Methcathinone Analogs, Mephedrone and Methylone, are Substrates for Monoamine Transporters in Brain Tissue

Abstract

The nonmedical use of 'designer' cathinone analogs, such as 4-methylmethcathinone (mephedrone) and 3,4-methylenedioxymethcathinone (methylone), is increasing worldwide, yet little information is available regarding the mechanism of action for these drugs. Here, we employed in vitro and in vivo methods to compare neurobiological effects of mephedrone and methylone with those produced by the structurally related compounds, 3,4-methylenedioxymethamphetamine (MDMA) and methamphetamine. In vitro release assays using rat brain synaptosomes revealed that mephedrone and methylone are nonselective substrates for plasma membrane monoamine transporters, similar to MDMA in potency and selectivity. In vivo microdialysis in rat nucleus accumbens showed that i.v. administration of 0.3 and 1.0 mg/kg of mephedrone or methylone produces dose-related increases in extracellular dopamine and serotonin (5-HT), with the magnitude of effect on 5-HT being greater. Both methcathinone analogs were weak motor stimulants when compared with methamphetamine. Repeated administrations of mephedrone or methylone (3.0 and 10.0 mg/kg, s.c., 3 doses) caused hyperthermia but no long-term change in cortical or striatal amines, whereas similar treatment with MDMA (2.5 and 7.5 mg/kg, s.c., 3 doses) evoked robust hyperthermia and persistent depletion of cortical and striatal 5-HT. Our data demonstrate that designer methcathinone analogs are substrates for monoamine transporters, with a profile of transmitter-releasing activity comparable to MDMA. Dopaminergic effects of mephedrone and methylone may contribute to their addictive potential, but this hypothesis awaits confirmation. Given the widespread use of mephedrone and methylone, determining the consequences of repeated drug exposure warrants further study.

Locomotor Stimulant and Rewarding Effects of Inhaling Methamphetamine, MDPV, and Mephedrone via Electronic Cigarette-Type Technology

“…Although the synthetic cathinone compounds MDPV and mephedrone are less well studied than MA, these compounds can stimulate motor activity in mice (Fantegrossi et al, 2013;Fuwa et al, 2009;Gatch et al, 2013) and rats Baumann et al, 2012Baumann et al, , 2013Huang et al, 2012;Wright et al, 2012) when administered by injection. MDPV appears to be approximately as potent as MA whereas mephedrone is less potent in most prior studies, and thus the relative potencies identified for vapor inhalation in this study (a threshold for effects at 12.5-25 mg/ml for MA and MDPV vs above 100 mg/ml for mephedrone, and significant differences in experiment 3 between mephedrone and the other two drugs) are roughly consistent with prior results using other routes of administration.…”

“…These drugs were selected because they span the range from traditional stimulant (MA) to entactogen (mephedrone) to restricted transporter inhibitor (MDPV) and thus the results would generalize across these subclasses (Simmler et al, 2013). Administration of each of these drugs by injection has been shown to increase activity of rats as measured by radiotelemetry Miller et al, 2013a;Wright et al, 2012), beam break (Baumann et al, 2012(Baumann et al, , 2013, or an activity wheel (Huang et al, 2012) in prior experiments, and therefore locomotor assessment is a valid approach for detecting in vivo effects of inhalation. Further experiments were conducted to determine whether intracranial self-stimulation (ICSS) reward thresholds are reduced by vapor exposure to stimulants, as has been reported following intraperitoneal (i.p.)…”

Human Pharmacology of Mephedrone in Comparison with MDMA

“…Studies in animal models indicate that mephedrone acts as a monoamine releaser and a reuptake inhibitor (Simmler et al, 2013;Baumann et al, 2012;López-Arnau et al, 2012). It has, therefore, been shown to increase dopamine in a similar manner to amphetamine and produce more serotonin increase (5-HT) than MDMA (Baumann et al, 2012;Kehr et al, 2011).…”

Psychoactive ‘Bath Salts’: Compounds, Mechanisms, and Toxicities

“…Using assay methods in rat brain synaptosomes, it has been shown that mephedrone and methylone act as substrates at plasma membrane transporters for norepinephrine, dopamine, and serotonin, thereby stimulating non-exocytotic release of these neurotransmitters (Baumann et al, 2012). Mephedrone is about two-times more potent than methylone as a transporter substrate.…”

“…Repeated subcutaneous (s.c.) administration of either drug to single-housed rats (3 or 10 mg/kg, three doses) has no longlasting effects on brain tissue monoamines (Baumann et al, 2012), but administration of higher doses of mephedrone to group-housed rats (10 or 25 mg/kg, s.c., four doses) causes selective depletion of brain serotonin (Hadlock et al, 2011). It is noteworthy that MDPV is the chief substance detected in blood and urine from patients hospitalized for bath salts overdose in the US (Spiller et al, 2011).…”