Mephedrone (4-methylmethcathinone) supports intravenous self-administration in Sprague-Dawley and Wistar rats

Abstract

Recreational use of the drug 4-methylmethcathinone (mephedrone; 4-MMC) became increasingly popular in the United Kingdom in recent years, spurred in part by the fact that it was not criminalized until April 2010. Although several fatalities have been associated with consumption of 4-MMC and cautions for recreational users about its addictive potential have appeared on Internet forums, very little information about abuse liability for this drug is available. This study was conducted to determine if 4-MMC serves as a reinforcer in a traditional intravenous self-administration model. Groups of male Wistar and Sprague-Dawley rats were prepared with intravenous catheters and trained to self-administer 4-MMC in 1-hour sessions. Per-infusion doses of 0.5 and 1.0 mg/kg were consistently self-administered, resulting in greater than 80% discrimination for the drug-paired lever and mean intakes of about 2-3 mg/kg/hour. Dose-substitution studies after acquisition demonstrated that the number of responses and/or the total amount of drug self-administered varied as a function of dose. In addition, radiotelemetry devices were used to show that self-administered 4-MMC was capable of increasing locomotor activity (Wistar) and decreasing body temperature (Sprague-Dawley). Pharmacokinetic studies found that the T1/2 of 4-MMC was about 1 hour in vivo in rat plasma and 90 minutes using in vitro liver microsomal assays. This study provides evidence of stimulant-typical abuse liability for 4-MMC in the traditional pre-clinical self-administration model.

Keywords: Cathinone; reinforcement; stimulant; thermoregulation.

Figure 1. Acquisition of 4-MMC self-administration: Reward-lever responses and reward-lever discrimination

A–D) Mean number of reward-lever responses and reward-lever selectivity (% reward-lever presses ÷ total lever presses) for: A) Sprague-Dawley rats trained to self-administer at 1.0 mg/kg/inf 4 (N =7). B) Sprague-Dawley rats trained to self-administer at 0.5 mg/kg/inf (N = 12). C) Wistar rats trained to self-administer at 1.0 mg/kg/inf (N = 11). D) Wistar rats trained to self-administer at 0.5 mg/kg/inf (N = 16). E–F) Mean number of reward-lever responses as a function of rat strain and per-infusion dose available during acquisition: E) Rats trained at 1.0 mg/kg/inf. F) Rats trained at 0.5 mg/kg/inf. Statistically reliable differences from the first session are indicated by * and differences between groups are represented by ^#. Error bars represent ±SEM.

Figure 2. Acquisition of 4-MMC self-administration: Body temperature and activity counts

AB) Mean body temperature (°C) across self-administration sessions (5-min time bins) as a function of cumulative dose per session (mg/kg) for: A) Sprague-Dawley rats trained on 1.0 mg/kg/inf (N = 9–12). B) Wistar rats trained on 0.5 mg/kg/inf (N = 11). C–D) Mean activity counts across self-administration sessions as a function of cumulative dose per session for: C) Sprague-Dawley rats trained on 1.0 mg/kg/inf (N = 9–12). D) Wistar rats trained on 0.5 mg/kg/inf (N = 11). Symbols: shaded = significantly different from the 0 timepoint (at which levers were extended) within dose; open = significantly different from the 0 timepoint within dose and from vehicle at that time bin; half-open = significantly different from vehicle at that time bin. Error bars represent ±SEM.

Figure 3. Fixed-ratio dose-response

Mean number of reward-lever responses (top) and cumulative drug intakes (mg/kg/session; bottom) for Sprague-Dawley rats (N = 7) (trained on 0.5 mg/kg/inf) as function of the per-infusion dose available. Data for sessions at the training dose three days before and three days after the dose-substitution sessions are included for comparison. A significant difference from both of the lower two dose-substitution conditions is indicated by the * symbol. Error bars represent ±SEM.

Figure 4. Progressive-ratio baseline sessions

Mean number of reward-lever responses and percent of total lever responses on the drug-paired lever per session (left panel) and the number of infusions per session (right panel) from Wistar rats (N = 14) under a progressive-ratio schedule of reinforcement (after initial acquisition at the per-infusion dose of 0.5 mg/kg/inf). Error bars represent ±SEM.

Figure 5. Progressive-ratio dose-response

Mean number of reward-lever responses and cumulative drug intakes for Wistar rats (N = 9) under a progressive-ratio schedule of reinforcement as a function of available per-infusion dose (mg/kg). Data for sessions at the training dose (0.5 mg/kg/inf) in the three days before dose-substitution sessions are included for comparison. A significant difference from both of the lower two dose conditions and vehicle is indicated by the * symbol. Error bars represent ±SEM.

Figure 6. Drug Substitution: 4-MMC in d-methamphetamine (MA)-trained rats

Mean number of reward-lever responses and cumulative drug intakes (mg/kg) of 4-MMC for a group of Sprague-Dawley rats (N = 8) trained to self-administer MA (0.1 mg/kg/inf; FR2). Data for the MA training dose in the three days before the dose-substitution are included for comparison. Statistically reliable differences from all other 4-MMC conditions are indicated by the * symbol, from 0.05–0.5 by the # symbol and from 0.05–0.1 by the & symbol. Error bars represent ±SEM.

Figure 7. Acquisition of METH and Vehicle self-administration: Reward-lever responses and reward-lever discrimination

Sprague-Dawley rats were trained to self-administer d-methamphetamine (METH) at 0.05 mg/kg/inf 4 (N =9) or vehicle only (N=8). Statistically reliable differences from the first three sessions are indicated by &, from the first session by * and differences between groups are represented by #. Error bars represent ±SEM.

Figure 8. Acquisition of 4-MMC following Vehicle self-administration: Reward-lever responses and reward-lever discrimination

The group of Sprague-Dawley rats trained to self-administer vehicle (N=8) for 15 sessions (upper panel) were thereafter permitted access to 4-MMC (0.5 mg/kg/inf) for 18 sessions (lower panel). In the upper panel, statistically reliable differences from the first three sessions are indicated by &, from the first session by * and differences between groups are represented by #. Reward lever responses and discrimination ratios in all 4-MMC sessions differed significantly from the V15 session. Error bars represent ±SEM.

Figure 9. Pharmacokinetics

Mean concentration of4-MMC in plasma following a bolus IV injection (1.0 mg/kg) in male Wistar and Sprague-Dawley rats (N =3 per strain). Error bars represent ±SEM.