Abuse-related and abuse-limiting effects of methcathinone and the synthetic "bath salts" cathinone analogs methylenedioxypyrovalerone (MDPV), methylone and mephedrone on intracranial self-stimulation in rats

Abstract

Rationale: Abuse of synthetic cathinones, popularized as "bath salts," has increased dramatically in the USA since their debut in 2010. Preclinical behavioral studies may clarify determinants of the abuse-related effects produced by these compounds.

Objectives: This study examined behavioral effects of (±)-methcathinone, (±)-3,4-methylenedioxypyrovalerone (MDPV), (±)-3,4-methylenedioxymethcathinone (methylone), and (±)-4-methylmethcathinone (mephedrone) in rats using intracranial self-stimulation (ICSS).

Methods: Male Sprague-Dawley rats (n = 18) with electrodes targeting the medial forebrain bundle responded for multiple frequencies of brain stimulation and were tested in two phases. First, dose-effect curves for methcathinone (0.1-1.0 mg/kg), MDPV (0.32-3.2 mg/kg), methylone (1.0-10 mg/kg), and mephedrone (1.0-10 mg/kg) were determined. Second, time courses were determined for effects produced by the highest dose of each compound.

Results: Methcathinone produced dose- and time-dependent facilitation of ICSS. MDPV, methylone, and mephedrone produced dose- and time-dependent increases in low rates of ICSS maintained by low brain stimulation frequencies, but also produced abuse-limiting depression of high ICSS rates maintained by high brain stimulation frequencies. Efficacies to facilitate ICSS were methcathinone ≥ MDPV ≥ methylone > mephedrone. Methcathinone was the most potent compound, and MDPV was the longest acting compound.

Conclusions: All compounds facilitated ICSS at some doses and pretreatment times, which is consistent with abuse liability for each of these compounds. However, efficacies of compounds to facilitate ICSS varied, with methcathinone displaying the highest efficacy and mephedrone displaying the lowest efficacy to facilitate ICSS.

Fig. 1

Effects of (±)-methcathinone, (±)-MDPV, (±)-methylone and (±)-mephedrone on full ICSS frequency-rate curves. Abscissae: frequency of electrical brain stimulation in log Hz. Ordinates: percent maximum control reinforcement rate (%MCR). Drug doses are indicated in legends in units of mg/kg. Filled points represent frequencies at which reinforcement rates were statistically different from vehicle rates as determined by two-way ANOVA followed by Holm-Sidak post hoc test, p<0.05. All data show mean ± SEM for five rats (methylone) or six rats (all other drugs).

Fig. 2

Time courses of (±)-methcathinone, (±)-MDPV, (±)-methylone and (±)-mephedrone effects on full ICSS frequency-rate curves. Drug doses are expressed in mg/kg and are indicated in front of the drug name in the title of each panel. Other details as in Figure 1.

Fig. 3

Summary of effects of (±)-methcathinone, (±)-MDPV, (±)-methylone and (±)-mephedrone on ICSS expressed as percent pre-drug baseline number of stimulations delivered across all frequencies of brain stimulation. Left panel (a) compares potencies and efficacies of drugs. Abscissa: drug dose in mg/kg. Ordinate: percent pre-drug baseline number of ICSS reinforcers. Right panel (b) compares time course profiles of drugs. Abscissa: pretreatment time in min. Ordinate: percent pre-drug baseline number of ICSS reinforcers.

Fig. 4

Rate-dependency analysis of methcathinone and its derivatives effects on ICSS. (a, b) Abscissae: log baseline ICSS rate. Ordinates: log percent baseline ICSS rate. Horizontal line at Y=2.0 indicates no change from baseline rates. Vertical line at X=1.0 indicates the position of the Y-intercept values used in Panel c. (c) Abscissa: drug dose in mg/kg. Ordinate: Y-intercept from linear regression analysis of rate-dependency plots. All points show mean data for 5–6 rats.