Methylone and Monoamine Transporters: Correlation with Toxicity

Abstract

Methylone (2-methylamino-1-[3,4-methylenedioxyphenyl]propane-1-one) is a synthetic hallucinogenic amphetamine analog, like MDMA (3,4-methylenedioxy- methamphetamine), considered to act on monoaminergic systems. However, the psychopharmacological profile of its cytotoxicity as a consequence of monoaminergic deficits remains unclear. We examined here the effects of methylone on the transporters for dopamine (DAT), norepinephrine (NET), and serotonin (SERT), using a heterologous expression system in CHO cells, in association with its cytotoxicity. Methylone inhibited the activities of DAT, NET, and SERT, but not GABA transporter-1 (GAT1), in a concentration-dependent fashion with a rank order of NET > DAT > SERT. Methylone was less effective at inhibiting DAT and NET, but more effective against SERT, than was methamphetamine. Methylone alone was not toxic to cells except at high concentrations, but in combination with methamphetamine had a synergistic effect in CHO cells expressing the monoamine transporters but not in control CHO cells or cells expressing GAT1. The ability of methylone to inhibit monoamine transporter function, probably by acting as a transportable substrate, underlies the synergistic effect of methylone and methamphetamine.

Powerful Cocaine-Like Actions of 3,4-Methylenedioxypyrovalerone (MDPV), a Principal Constituent of Psychoactive ‘Bath Salts’ Products

“…In particular, MDPV and cocaine exhibit lowefficacy 'partial'-releasing actions at DAT and NET (ie,o30% of maximal release), whereas amphetamine, mephedrone, and methylone are fully efficacious in their ability to evoke release of preloaded [ 3 H]MPP þ and [ 3 H]serotonin (ie, 100% of maximal release). The data with mephedrone and methylone agree with the published findings showing that these bath salts compounds are transporter substrates and not blockers (Baumann et al, 2012;Nagai et al, 2007;Sogawa et al, 2011). Based on previous observations, we surmised that the apparent releasing effects of MDPV and cocaine are secondary to uptake blockade, rather than substrate activity per se.…”

“…3,4-Methylenedioxypyrovalerone and monoamine transporters MH Baumann et al there are conflicting reports in the literature regarding the precise interactions of designer cathinones with monoamine transporters (Baumann et al, 2012;Cozzi et al, 1999;Hadlock et al, 2011;Martinez-Clemente et al, 2011;Nagai et al, 2007;Sogawa et al, 2011). Our results from in vitro experiments in synaptosomes confirm that uptake inhibition assays can identify drugs which interact with transporter proteins.…”

The Toxicology of Bath Salts: A Review of Synthetic Cathinones

“…Interestingly, inhibition of NE reuptake was competitive, while inhibition at serotonin and dopamine receptors was noncompetitive [44]. Additionally, methylone inhibition may cause reverse transport of neurotransmitters from the nerve terminal into the synapse, as is described with methamphetamine [46].…”

“…Methylone was found to be equally as potent as methamphetamine and MDMA at inhibiting reuptake of norepinephrine and dopamine in human platelets due to inhibition of monoamine uptake transporters [44,46]. There is some controversy in the literature about its potency at serotonin reuptake inhibition compared to other amphetamine derivatives, with several studies finding decreased potency and at least one study finding no difference [44,46,47].…”

“…There is some controversy in the literature about its potency at serotonin reuptake inhibition compared to other amphetamine derivatives, with several studies finding decreased potency and at least one study finding no difference [44,46,47]. Methylone was significantly less potent at VMAT2 receptor inhibition than methamphetamine and MDMA [44].…”