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Effects of social interaction and warm ambient temperature on brain hyperthermia induced by the designer drugs methylone and MDPV.

ABSTRACT: 3,4-Methylenedioxymethcathinone (methylone) and 3,4-methylenedioxypyrovalerone (MDPV) are new drugs of abuse that have gained worldwide popularity. These drugs are structurally similar to 3,4-methylenedioxymethamphetamine (MDMA) and share many of its physiological and behavioral effects in humans, including the development of hyperthermia during acute intoxication. Here, we examined the effects of methylone (1-9 mg/kg, s.c.) or MDPV (0.1-1.0 mg/kg, s.c.) on brain temperature homeostasis in rats maintained in a standard laboratory environment (single-housed in a quiet rest at 22 °C) and under conditions that model human drug use (social interaction and 29 °C ambient temperature). By simultaneously monitoring temperatures in the nucleus accumbens, temporal muscle, and facial skin, we assessed the effects of methylone and MDPV on intra-brain heat production and cutaneous vascular tone, two critical factors that control brain temperature responses. Both methylone and MDPV dose-dependently increased brain temperature, but even at high doses that induced robust locomotor activation, hyperthermia was modest in magnitude (up to ∼2 °C). Both drugs also induced dose-dependent peripheral vasoconstriction, which appears to be a primary mechanism determining the brain hyperthermic responses. In contrast to the powerful potentiation of MDMA-induced hyperthermia by social interaction and warm ambient temperature, such potentiation was absent for methylone and minimal for MDPV. Taken together, despite structural similarities to MDMA, exposure to methylone or MDPV under conditions commonly associated with human drug use does not lead to profound elevations in brain temperature and sustained vasoconstriction, two critical factors associated with MDMA toxicity.

SUBMITTER: Kiyatkin EA

PROVIDER: S-EPMC4443958 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:BackgroundAmphetamine analogs with a 3,4-methylenedioxy ring-substitution are among the most popular illicit drugs of abuse, exerting stimulant and entactogenic effects. Enzymatic N-demethylation or opening of the 3,4-methylenedioxy ring via O-demethylenation gives rise to metabolites that may be pharmacologically active. Indeed, previous studies in rats show that specific metabolites of 3,4-methylenedioxymethamphetamine (MDMA), 3,4-methylenedioxymethcathinone (methylone) and 3,4-methylenedioxypyrovalerone (MDPV) can interact with monoaminergic systems.AimInteractions of metabolites of MDMA, methylone and MDPV with human monoaminergic systems were assessed.MethodsThe ability of parent drugs and their metabolites to inhibit uptake of tritiated norepinephrine, dopamine and serotonin (5-HT) was assessed in human embryonic kidney 293 cells transfected with human monoamine transporters. Binding affinities and functional activity at monoamine transporters and various receptor subtypes were also determined.ResultsMDMA and methylone displayed greater potency to inhibit norepinephrine uptake as compared to their effects on dopamine and 5-HT uptake. N-demethylation of MDMA failed to alter uptake inhibition profiles, whereas N-demethylation of methylone decreased overall transporter inhibition potencies. O-demethylenation of MDMA, methylone and MDPV resulted in catechol metabolites that maintained norepinephrine and dopamine uptake inhibition potencies, but markedly reduced activity at 5-HT uptake. O-methylation of the catechol metabolites significantly decreased norepinephrine uptake inhibition, resulting in metabolites lacking significant stimulant properties.ConclusionsSeveral metabolites of MDMA, methylone and MDPV interact with human transporters and receptors at pharmacologically relevant concentrations. In particular, N-demethylated metabolites of MDMA and methylone circulate in unconjugated form and could contribute to the in vivo activity of the parent compounds in human users.

Project description:BackgroundWe hypothesized that exposure to temperatures above the thermoneutral zone (TNZ) would decrease food intake in young adults in a sedentary office environment over a 2-h period.MethodsParticipants wearing standardized clothing were randomized to perform routine office work in the TNZ, considered control (19-20°C), or above the TNZ considered warmer (26-27°C) using a parallel-group design (n = 11 and 9, respectively). Thermal images of the inner canthus of their eye and middle finger nail bed, representing proxies of core and peripheral temperatures, respectively, were taken at baseline, first, and second hour during this lunchtime study. Heat dissipation was estimated using peripheral temperature. General linear models were built to examine the effects of thermal treatment on caloric intake and potential mediation by heat dissipation. Researchers conducted the trial registered as NCT02386891 at Clinicaltrials.gov during April to May 2014.ResultsDuring the 2-h stay in different ambient temperatures, the participants in the control conditions ate 99.5 kcal more than those in the warmer conditions; however, the difference was not statistically significant. Female participants ate about 350 kcal less than the male participants (p = 0.024) in both groups and there was no significant association between caloric intake and participant's body mass index (BMI). After controlling for thermal treatment, gender and BMI, the participant's peripheral temperature was significantly associated with caloric intake (p = 0.002), suggesting a mediating effect. Specifically, for every 1°C increase in peripheral temperature suggesting increased heat dissipation, participants ate 85.9 kcal less food.ConclusionThis pilot study provided preliminary evidence of effects of thermal environment on food intake. It suggests that decreased food intake in the experimental (warmer) environment is potentially mediated through thermoregulatory mechanisms.

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Effects of social interaction and warm ambient temperature on brain hyperthermia induced by the designer drugs methylone and MDPV.

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