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 (4× 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.

Fig. 1.

Repeated mephedrone injections rapidly (within 1 h) decrease hippocampal synaptosomal 5HT uptake (A) and striatal synaptosomal DA uptake (B). Rats received mephedrone (4× 10 or 25 mg/kg s.c. per injection, 2-h intervals) or saline (1 ml/kg s.c. per injection, 2-h intervals) and were sacrificed 1 h after the final injection. Columns represent means, and vertical lines represent 1 S.E.M. determinations in 6–10 rats.*, p ≤ 0.05, significant difference from saline controls.

Fig. 2.

Repeated mephedrone injections cause persistent decreases in hippocampal synaptosomal 5HT uptake (A) and hippocampal 5HT content (B), but not in striatal synaptosomal DA uptake (C) or striatal DA content (D) as assessed 7 days after treatment. Rats received mephedrone (4× 10 or 25 mg/kg s.c. per injection, 2-h intervals) or saline vehicle (1 ml/kg s.c. per injection, 2-h intervals) and were sacrificed 7 days later. Tissues were assayed as described in “Synaptosomal [³H]DA and [³H]5HT Uptake” and “DA and 5HT Concentrations” (under Materials and Methods). Columns represent the means, and vertical lines represent 1 S.E.M. determinations in 6 to 10 rats.*, p ≤ 0.05, significant difference from all of the other groups.

Fig. 3.

Mephedrone causes DA release from a striatal suspension. A 5.0 μM concentration of METH, mephedrone, or MDMA was applied to a striatal suspension that was preloaded with DA (see Materials and Methods; n = 7–11). The initial velocities of DA release (determined over the first 3 s) for METH, mephedrone, and MDMA were 0.29 ± 0.01*, 0.25 ± 0.01*, and 0.16 ± 0.01* nmol/(s · g tissue wet weight), respectively [F_(2,4071) = 85.2509; *, p ≤ 0.05, significant difference from all of the other groups]. The maximal DA release for METH, mephedrone, and MDMA were 3.8 ± 0.6*, 2.7 ± 0.2*, and 1.7 ± 0.2* nmol/g tissue weight, respectively. *, p ≤ 0.05, significant difference from all of the other groups.

Fig. 4.

Mephedrone (A) and METH (B) are self-administered by rats. Rats were food-trained as described under Materials and Methods. After catheter implantation, rats were given access (4-h sessions, 7–8 days) to saline (10 μl per infusion), mephedrone (0.24 mg per 10-μl infusion), or METH (0.24 mg per 10-μl infusion) according to an FR1 schedule of reinforcement as described under Materials and Methods. *, p ≤ 0.05, significant difference from saline controls.