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/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.

Effects of Social Interaction and Warm Ambient Temperature on Brain Hyperthermia Induced by the Designer Drugs Methylone and MDPV

“…However, the vasoconstrictive effects of methylone and MDPV were weaker and significantly shorter in duration than those of MDMA. Consistent with previous studies in rats (Baumann et al, 2012;Aarde et al, 2013), MDPV was at least 10-fold more potent than methylone at inducing hyperthermia, vasoconstriction, and motor activation. These differences in drug potency are likely due to the greater affinity of MDPV for monoamine transporters, the primary targets of stimulant drug action in the brain (Baumann et al, 2013b).…”

“…It is important to note that our present results and previous findings in rodent models (Baumann et al, 2012;Aarde et al, 2013;Fantegrossi et al, 2013) do not necessarily imply that these 'bath-salt' drugs cannot induce serious health complications in humans (eg, see Introduction). Although animal experiments are essential to examine the effects of drugs under controlled conditions and to explore underlying mechanisms, significant issues such as between- species dose equivalency remain in translating work done in rodent models to humans.…”

“…By contrast, MDPV is a potent transporter blocker that inhibits the uptake of dopamine and norepinephrine, with minimal effects on serotonin uptake (Baumann et al, 2013b;Cameron et al, 2013). Both drugs increase extracellular dopamine in the nucleus accumbens (NAc) of rats (Baumann et al, 2012(Baumann et al, , 2013b and are readily self-administered (Aarde et al, 2013;Watterson et al, 2014), suggesting that their chronic use can lead to addiction.…”

“…In humans, robust increases in body temperature have been reported during acute intoxication with both methylone (Pearson et al, 2012) and MDPV (Borek and Holstege, 2012;Murray et al, 2012;Kesha et al, 2013). Despite such clinical evidence, the reported temperature effects of methylone and MDPV in laboratory animals are controversial, varying according to species, age, dose, and experimental conditions (Baumann et al, 2012;Aarde et al, 2013;Fantegrossi et al, 2013;Merluzzi et al, 2013). Repeated methylone (3-10 mg/kg, subcutaneously (s.c.)) injections increase core temperature in rats (Baumann et al, 2012), but such elevations are less than those induced by MDMA.…”

“…but only at elevated ambient temperature (Fantegrossi et al, 2013). In rats, acute MDPV (1.0-5.6 mg/kg, s.c.) has no effect on core temperature (Aarde et al, 2013). Thus, it remains unclear whether methylone and MDPV affect temperature homeostasis in rodents, and how the effects of these drugs are modulated under conditions that mimic human drug use.…”