4-Methylmethcathinone (Mephedrone): Neuropharmacological Effects of a Designer Stimulant of Abuse

Abstract

The designer stimulant 4-methylmethcathinone (mephedrone) is among the most popular of the derivatives of the naturally occurring psychostimulant cathinone. Mephedrone has been readily available for legal purchase both online and in some stores and has been promoted by aggressive Web-based marketing. Its abuse in many countries, including the United States, is a serious public health concern. Owing largely to its recent emergence, there are no formal pharmacodynamic or pharmacokinetic studies of mephedrone. Accordingly, the purpose of this study was to evaluate effects of this agent in a rat model. Results revealed that, similar to methylenedioxymethamphetamine, methamphetamine, and methcathinone, repeated mephedrone injections (4ϫ 10 or 25 mg/kg s.c. per injection, 2-h intervals, administered in a pattern used frequently to mimic psychostimulant "binge" treatment) cause a rapid decrease in striatal dopamine (DA) and hippocampal serotonin (5-hydroxytryptamine; 5HT) transporter function. Mephedrone also inhibited both synaptosomal DA and 5HT uptake. Like methylenedioxymethamphetamine, but unlike methamphetamine or methcathinone, repeated mephedrone administrations also caused persistent serotonergic, but not dopaminergic, deficits. However, mephedrone caused DA release from a striatal suspension approaching that of methamphetamine and was self-administered by rodents. A method was developed to assess mephedrone concentrations in rat brain and plasma, and mephedrone levels were determined 1 h after a binge treatment. These data demonstrate that mephedrone has a unique pharmacological profile with both abuse liability and neurotoxic potential.

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

“…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.…”

Mephedrone pharmacokinetics after intravenous and oral administration in rats: relation to pharmacodynamics

“…Plasma samples were extracted as described above. The extraction 7 of brain samples was carried out as described by Hadlock et al (2011) and brain mephedrone levels and protein binding assays were quantified as described in the pharmacokinetic experiments.…”

“…In this study mephedrone was administered orally and urine was collected over a 24-hour period. Hadlock et al (2011) assessed mephedrone concentrations in rat brain and plasma 1 h after a binge treatment and more recently (Khreit et al 2012) investigated the in vitro metabolism of mephedrone in rat isolated hepatocytes.…”

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

“…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).…”

“…The fact that synthetic cathinones enhance dopamine transmission predicts high abuse liability. Hadlock et al (2011) reported that i.v. mephedrone (0.24 mg/infusion) is readily self-administered by rats, but reinforcing effects of other synthetic cathinones are largely unexplored.…”