In vivo Effects of Abused ‘Bath Salt’ Constituent 3,4-methylenedioxypyrovalerone (MDPV) in Mice: Drug Discrimination, Thermoregulation, and Locomotor Activity

Abstract

In recent years, synthetic analogues of naturally occurring cathinone have emerged as psychostimulant-like drugs of abuse in commercial 'bath salt' preparations. 3,4-Methylenedioxypyrovalerone (MDPV) is a common constituent of these illicit products, and its structural similarities to the more well-known drugs of abuse 3,4-methylenedioxymethamphetamine (MDMA), and methamphetamine (METH) suggest that it may have similar in vivo effects to these substances. In these studies, adult male NIH Swiss mice were trained to discriminate 0.3 mg/kg MDPV from saline, and the interoceptive effects of a range of substitution doses of MDPV, MDMA, and METH were then assessed. In separate groups of mice, surgically implanted radiotelemetry probes simultaneously monitored thermoregulatory and locomotor responses to various doses of MDPV and MDMA, as a function of ambient temperature. We found that mice reliably discriminated the MDPV training dose from saline and that cumulative doses of MDPV, MDMA, and METH fully substituted for the MDPV training stimulus. All three drugs had similar ED 50 values in this procedure. Stimulation of motor activity was observed following administration of a wide range of MDPV doses (1-30 mg/kg), and the warm ambient temperature potentiated motor activity and elicited profound stereotypy and self-injurious behavior at 30 mg/kg. In contrast, MDPV-induced hyperthermic effects were observed in only the warm ambient environment. This pattern of effects is in sharp contrast to MDMA, where ambient temperature interacts with thermoregulation, but not locomotor activity. These studies suggest that although the interoceptive effects of MDPV are similar to those of MDMA and METH, direct effects on thermoregulatory processes and locomotor activity are likely mediated by different mechanisms than those of MDMA.

Trace Amine-Associated Receptor 1 Regulation of Methamphetamine Intake and Related Traits

“…Instead, heightened sensitivity to MA-induced hypothermia was associated with low MA intake and greater sensitivity to MA-induced aversion. MA is an agonist at TAAR1 (Bunzow et al, 2001;Reese et al, 2014;Wolinsky et al, 2007) and the outcome of hypothermia is in agreement with other reports of TAAR1 agonist-induced hypothermia in rodents (Di Cara et al, 2011;Fantegrossi et al, 2013;Panas et al, 2010;Sabol et al, 2013). Thus, it appears that TAAR1 mediates MA-induced hypothermia and that the immediate hypothermic effect of MA may have a role in curbing MA intake in MALDR, Taar1 +/+ and Taar1 +/ − mice.…”

“…Acute and chronic MA can induce hyperthermia (Bowyer et al, 1994;Sabol et al, 2013), but hypothermia may occur at lower doses and 18-20°C ambient temperatures (Sabol et al, 2013). MA-induced hypothermia may be partly regulated by TAAR1, since other TAAR1 agonists induce hypothermia (Di Cara et al, 2011;Fantegrossi et al, 2013;Panas et al, 2010), and Taar1 − / − mice do not exhibit hypothermia to doses of the MA-like drug, MDMA, that induce hypothermia in +/+ mice (Di Cara et al, 2011). Likewise, Taar1 − / − mice do not display hypothermia to MA, but the dose of MA used in this published study did not induce hypothermia in +/+ mice (Panas et al, 2010), so further study is needed.…”

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

“…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.…”

“…MDPV is reported to cause hyperthermia in mice (3-30 mg/kg, i.p.) 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).…”

“…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.…”