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/hour; 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/hr) 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.

BACKGROUND Reports from US, UK and European drug policy entities, and ongoing media accounts, show increasing recreational use of 4-methylmethcathinone (4-MMC, mephedrone) and 3,4-methylenedioxypyrovalerone (MDPV). Severe sympathomimetic symptoms, hallucinations, psychoses, and even deaths have been reported, yet little scientific information is available on the effects of these compounds in laboratory models. Available studies on the neurochemistry of these drugs show that 4-MMC and MDPV enhance DA neurotransmission, while 4-MMC additionally enhances 5-HT neurotransmission- a pattern much like that reported for methamphetamine vs. 3,4-methylenedioxymethamphetamine (MDMA). As is the case for designer amphetamines, these neurochemical distinctions may predict differential potential for repetitive versus episodic abuse and distinct lasting toxicities. METHODS This study determined relative locomotor stimulant effects of 4-MMC (1–10 mg/kg, s.c.) and MDPV (0.5–5.6 mg/kg, s.c.), in comparison with d-methamphetamine (MA; 0.5–5.6 mg/kg, s.c.) and MDMA (1–7.5 mg/kg, s.c.) on a measure of locomotor activity – voluntary wheel running – in male Wistar rats (N=8). RESULTS Compared to counts of wheel rotations after saline, a biphasic change in the pattern of counts was observed after injections of MA and MDPV, with relatively higher counts following lower doses and lower counts following the highest dose. However, monophasic, dose-dependent reductions in counts were observed in response to injections of MDMA and 4-MMC. CONCLUSION Thus, voluntary wheel running yielded the same categorical distinctions for these drugs as did prior experiments testing the effects of these drugs on monoaminergic neurotransmission. These data indicate that MDPV produces prototypical locomotor stimulant effects whereas 4-MMC is more similar to the entactogen MDMA.

Rationale Lack of access to conventional sources of reinforcement has been proposed as a risk factor for substance abuse in lower socio-economic populations. There is laboratory evidence that behavioral alternatives (enrichment or exercise) and alternative reinforcers (e.g., sweetened solutions) can reduce self-administration of a variety of drugs. Objectives To determine if drug self-administration could devalue wheel activity in an animal model. Methods Male Wistar rats were trained to self-administer 3,4-methylenedioxypyrovalerone (MDPV; “bath salts”), 0.05 mg/kg/infusion, i.v., with concurrent access to a running wheel that was either locked (LW) or unlocked (UW). Results MDPV intake steadily increased across the 20 session acquisition interval but did not differ significantly between UW and LW groups. Mean wheel rotations declined significantly across the acquisition interval in the UW group. Of the rats that acquired self-administration, 60% engaged in a binge-like behavior at the initiation of acquisition - intake was limited only by post-reinforcement timeout. The Binge rats had higher post acquisition levels of drug intake (even after excluding the binge session) and the UW Binge rats showed a precipitous post-acquisition drop in wheel activity that was not observed in the UW No-Binge rats. Conclusions These data confirm that MDPV is a powerful reward/reinforcer and show that a relatively high rate of intake at the onset of drug taking can devalue natural rewards (wheel activity) and can predict higher subsequent drug intake levels. Thus, limiting the intensity of initial drug exposure may attenuate subsequent drug abuse/addiction by preventing the devaluation of natural alternative rewards/reinforcers.

Rationale MDMA alters body temperature in rats with a direction that depends on the ambient temperature (TA). The thermoregulatory effects of MDMA and TA may affect intravenous self-administration (IVSA) of MDMA but limited prior reports conflict. Objective To determine how body temperature responses under high and low TA influence MDMA IVSA. Methods Male Sprague-Dawley rats were trained to IVSA MDMA (1.0 mg/kg/infusion; 2-hr sessions; FR5 schedule of reinforcement) under TA 20°C or 30°C. Radiotelemetry transmitters recorded body temperature and activity during IVSA. Results MDMA intake increased under both TA during acquisition, but to a greater extent in the 30°C group. The magnitude of hypothermia was initially equivalent between groups but diminished over training in the 30°C group. Within-session activity was initially lower in the 30° C group, but by the end of acquisition and maintenance, activity was similar for both groups. When TA conditions were swapped, the hot-trained group increased MDMA IVSA under 20 °C TA and a modest decrease in drug intake was observed in the cold-trained group under 30 °C TA. Subsequent non-contingent MDMA (1.0–5.0 mg/kg, i.v.) found that rats with higher MDMA IVSA rates showed blunted hypothermia compared with rats with lower IVSA levels; however, within-session activity did not differ by group. High TA increased intracranial self-stimulation thresholds in a different group of rats and MDMA reduced thresholds below baseline at low, but not high, TA. Conclusions High TA appears to enhance acquisition of MDMA IVSA through an aversive effect and not via thermoregulatory motivation.

Results: MDMA intake increased under both T A during acquisition, but to a greater extent in the 30°C group. The magnitude of hypothermia was initially equivalent between groups but diminished over training in the 30°C group. Within-session activity was initially lower in the 30° C group, but by the end of acquisition and maintenance, activity was similar for both groups. When T A conditions were swapped, the hot-trained group increased MDMA IVSA under 20 °C T A and a modest decrease in drug intake was observed in the cold-trained group under 30 °C T A . Subsequent non-contingent MDMA (1.0-5.0 mg/kg, i.v.) found that rats with higher MDMA IVSA rates showed blunted hypothermia compared with rats with lower IVSA levels; however, within-session activity did not differ by group. High T A increased intracranial self-stimulation thresholds in a different group of rats and MDMA reduced thresholds below baseline at low, but not high, T A . Conclusions:High T A appears to enhance acquisition of MDMA IVSA through an aversive effect and not via thermoregulatory motivation.