The novel recreational drug 3,4-methylenedioxypyrovalerone (MDPV) is a potent psychomotor stimulant: self-administration and locomotor activity in rats

Abstract

Recreational use of the cathinone derivative 3,4-methylenedioxypyrovalerone (MDPV; "bath salts") has increased worldwide in past years, accompanied by accounts of health and legal problems in the popular media and efforts to criminalize possession in numerous jurisdictions. Minimal information exists on the effects of MDPV in laboratory models. This study determined the effects of MDPV, alongside those of the better studied stimulant d-methamphetamine (METH), using rodent models of intravenous self-administration (IVSA), thermoregulation and locomotor activity. Male Wistar rats were trained to self-administer MDPV or METH (0.05 mg/kg/infusion, i.v.) or were prepared with radiotelemetry implants for the assessment of body temperature and activity responses to MDPV or METH (0-5.6 mg/kg s.c.). METH and MDPV were consistently self-administered within 10 training sessions (mg/kg/h; METH Mean = 0.4 and Max = 1.15; MDPV Mean = 0.9 and Max = 5.8). Dose-substitution studies demonstrated that behavior was sensitive to dose for both drugs, but MDPV (0.01-0.50 mg/kg/inf) showed greater potency and efficacy than METH (0.1-0.25 mg/kg/inf). In addition, both MDPV and METH increased locomotor activity at lower doses (0.5-1.0 mg/kg, s.c.) and transiently decreased activity at the highest dose (5.6 mg/kg, s.c.). Body temperature increased monotonically with increasing doses of METH but MDPV had a negligible effect on temperature. Stereotypy was associated with relatively high self-administered cumulative doses of MDPV (∼1.5 mg/kg/h) as well as with non-contingent MDPV administration wherein the intensity and duration of stereotypy increased as MDPV dose increased. Thus, MDPV poses a substantial threat for compulsive use that is potentially greater than that for METH.

Figure 1

Route for MDPV synthesis

Figure 2

Infusion Rate (filled symbols; inf/hr; 0.05 mg/kg/inf)and lever discrimination (unfilled symbols; value = 100% * drug-paired lever presses/total lever presses; lever presses during post-reinforcement time out not included) of MDPV (N=13) or METH (N=9) under a fixed-ratio schedule of reinforcement (FR5) as a function of self-administration session (1^st 3 sessions under food restriction).For the effect of session, significant differences between pairs of means are indicated by a # symbol. Error bars represent SEM.

Figure 3

Fixed-ratio (FR5), dose-response testing. Means of infusion rate (infusions/hr; Graph A) and post-reinforcement pause length (average time in seconds between an infusion and the next correct response; Graph B) as a function of the type of drug available (MDPV, N=10; METH, N=9) and per-infusion dose (mg/kg). For comparisons between drug types as a function of per-infusion dose, significant differences are indicted by the “*” symbol. For the effect of per-infusion dose as a function of drug type, significant post hoc comparisons are indicted by the “#” symbol for MDPV and the “@” symbol for METH. Error bars represent SEM. Also, infusion number as a function of the time within the session that that infusion occurred (Graph C) are presented to show records of individual rats’ behavior within each session. Within a particular drug type, each unique symbol represents a specific subject. For each per-infusion dose, each session of a particular subject at that dose is represented by a single curve.

Figure 4

Progressive-ratio, dose-response testing (ratio = 5e^{[injection#*j]}, except for 1^st ratio which was always 1; MDPV, j = 0.4; METH, j = 0.3). Means of total correct lever presses (1^st 3 hours of the session only; includes lever presses during post-reinforcement time out; Graph A) and post-reinforcement pause length (average time in seconds between an infusion and the next correct response; 1^st 3 hours of the session only; Graph B) as a function of the type of drug available (MDPV, N=8; METH, N=7) and per-infusion dose (mg/kg). For comparisons between drug types as a function of per-infusion dose, significant differences are indicted by the “*” symbol. For the effect of per-infusion dose as a function of drug type, significant post hoc comparisons are indicted by the “#” symbol for MDPV. Error bars represent SEM.

Figure 5

A) Average locomotor activity (% change in activity counts from 30-min pre-injection interval)and body temperature (°C) in 30-min time intervals (“bins”) as a function of injection dose and time from injection (s.c.) of either MDPV (N=8) or METH (N=7). Top Graphs: Locomotor activity after injection of MDPV under a room temperature of 23±1 °C (Left) or METH under room temperatures of 20±2 °C or 25±2 °C (Three Rightmost; the first of which shows the data pooled across room temperatures; the effect of room temperature was not significant nor did it interact with other factors). Bottom Graphs: Body temperature after injection of MDPV under a room temperature of 23±1 °C (Left) or METH under room temperatures of 20±2 °C or 25±2 °C (Three Rightmost – the first of which shows the data pooled across room temperatures of 20±2 °C and 25±2 °C; 3-way interaction was not significant; other 2-way interactions graphed in “C”). B) Means for area under the curve (AUC) calculations (summed deviations from the mean of vehicle) for locomotor activity (Left) and body temperature (Right) as functions of drug type. C) Body temperature after METH injections. Left Graph: Effect of injection dose as a function of room temperature. Middle Graph: Effect of room temperature as a function of injection dose. Right Graph: Effect of room temperature as a function of time from injection. Symbols (all graphs): For the effect of time, mean values that were significantly different from the baseline mean within dose or room temperature are indicated by open symbols. For the effect of dose (mg/kg),mean values that were significantly different are indicated by the following symbols: α= vehicle vs. 0.5; β = vehicle vs. 1.0; δ = vehicle vs. 3.2; ψ = vehicle vs. 5.6; ¢ = 0.5 vs. 1.0; $ = 0.5 vs. 3.2; € = 0.5 vs. 5.6; * = 1.0 vs. 3.2; # = 1.0 vs. 5.6; § = 3.2 vs. 5.6. For the effect of drug type and room temperature, significant differences are indicated by the “*” symbol. Error bars represent SEM.

Figure 6

Stereotypy. Left Graph: Cumulative dose (mg/kg; N = 10) as a function of the observation of post-session stereotypy (repetitive behaviors: biting, licking and sniffing) after self-administration sessions (1 hour per session; FR5) (*p < 0.01). Right Graph: Stereotypy scores (range of 0–2; N=8) as a function of injection dose of MDPV and time from injection in 15 min time bins. For the effect of time, mean values that significantly different from the first observation period (immediately after injection) within dose are indicated by open symbols. For the effect of dose (mg/kg), mean values that significantly differed as a function of time are indicated by the following symbols: α= vehicle vs. 0.5; β = vehicle vs. 1.0; δ = vehicle vs. 3.2; ψ = vehicle vs. 5.6; ¢ = 0.5 vs. 1.0; $ = 0.5 vs. 3.2; € = 0.5 vs. 5.6; * = 1.0 vs. 3.2; # = 1.0 vs. 5.6; § = 3.2 vs. 5.6.Error bars represent SEM.