Mephedrone and methylenedioxypyrovalerone (MDPV), major constituents of "bath salts," produce opposite effects at the human dopamine transporter

Abstract

Rationale: Psychoactive "bath salts" represent a relatively new drug of abuse combination that was placed in Schedule I in October 2011. Two common ingredients of bath salts include the cathinone analogs: mephedrone and methylenedioxypyrovalerone (MDPV). The mechanism of action of these synthetic cathinone analogs has not been well investigated.

Materials and methods: Because cathinone and methcathinone are known to act as releasing agents at the human dopamine transporter (hDAT), mephedrone and MDPV were investigated at hDAT expressed in Xenopus oocytes.

Results: Whereas mephedrone was found to have the signature of a dopamine-releasing agent similar to methamphetamine or methcathinone, MDPV behaved as a cocaine-like reuptake inhibitor of dopamine.

Conclusions: Mephedrone and MDPV produce opposite electrophysiological signatures through hDAT expressed in oocytes. Implications are that the combination (as found in bath salts) might produce effects similar to a combination of methamphetamine and cocaine.

Figure 1

Chemical structures of the phenylisopropylamine stimulants amphetamine (AMPH) and methamphetamine (METH), and their corresponding phenylpropanon-amine counterparts cathinone (CATH) and methcathinone (MCAT), as compared to the structures of the cathinone analogs mephedrone (MEPH) and 3,4-methylenedioxy-pyrovalerone (MDPV). It might be noted that the spatial configuration of S(−)cathinone and S(−)methcathinone correspond to that of the S(+)-isomers of amphetamine and methamphetamine.

Figure 2

Sample currents generated in hDAT by application of 10 μM S-methamphetamine (S-METH; A), S-methcathinone (S-MCAT; B), and mephedrone (MEPH; C) at −60 mV. The effect of 10 μM dopamine (DA; D) is shown for comparison and all traces are normalized to the DA peak current for comparison.

Figure 3

Dose response curves (±SEM) for S-methamphetamine (S-METH; triangles), S-methcathinone (S-MCAT; squares), and mephedrone (MEPH; circles) in hDAT at −60 mV. Data points were obtained by exposing hDAT-expressing oocytes to different concentrations of drug for 1 min and measuring peak currents (n = 5 to 9 at each concentration). Drug responses are expressed as a percentile of DA pre-pulse peak current (100%) in each experiment.

Figure 4

Application of different concentrations of MDPV or cocaine (COC) to hDAT-expressing Xenopus oocytes voltage clamped at −60 mV (n = 5 to 6 at each concentration). Drug responses are expressed as a percentile of DA pre-pulse peak current (100%) in each experiment.

Figure 5

Application of S-methamphetamine (S-METH) or mephedrone (MEPH) (10 μM) followed by application of either cocaine (COC) (A and B) or MDPV (C) (10 μM) to hDAT-expressing Xenopus oocytes voltage clamped at -60 mV. All traces are normalized to the S-METH peak current for comparison.

Figure 6

(A) Raw traces for cocaine (COC) dose-inhibition curve: 5 μM dopamine (DA) applied for 30 sec (solid line) followed by perfusion of 5 μM DA plus various concentrations of COC (dashed line, see panel C for concentration range). Xenopus oocytes voltage clamped at −60 mV. (B) Raw traces for MDPV dose-inhibition under the same oocyte conditions as (A). Unlike COC, MDPV inhibition did not reach a steady state level within 1 min. The inhibitory effect at all MDPV concentrations persisted maximum inhibition is reached (for the lowest concentrations, 0.5 μM, it takes more than 5 min to reach steady state; in contrast, the highest concentration of MDPV (10 μM) reaches the steady state in 15 sec). (C) Cumulative data from (A) (±SEM) for cocaine. Each drug concentration was applied in the presence of dopamine (5 μM). Data were obtained by exposing hDAT-expressing oocytes to different concentrations of drug and measuring the relative return to the baseline 60 sec after test drug was applied (n = 5 to 9 at each concentration). A similar curve for MDPV was unattainable because at the low concentrations 0.5 and 1.0 μM steady state currents were not reached.