Gender differences in tolerance to the hyperthermia mediated by the synthetic cathinone methylone

The toxidrome associated with death from the synthetic cathinones includes hyperthermia as part of the sympathomimetic syndrome. Here, we examine the gender differences in the development of tolerance to the hyperthermia mediated by the synthetic cathinone methylone. In addition to temperature changes, expression differences in genes encoding the uncoupling proteins (UCP) 1 & 3, and TGR5 in skeletal muscle (SKM) and brown adipose tissue (BAT) were examined. Male and female rats were treated weekly with methylone (10 mg/kg). The females developed a tolerance to the methylone-induced hyperthermia by week two of drug exposure. By the third week, females displayed a hypothermic response to methylone. Conversely, males continued to display a hyperthermic response up to and including week four. At week four, the males demonstrated a significantly lower hyperthermia and a complete tolerance seen at week five with no significant hyperthermia. Tissue samples collected after treatment on the sixth week indicate that chronic exposure to methylone reduced UCP1 expression in SKM and BAT of the female rats. Only the females displayed increased TGR5 expression in BAT. UCP3 expression increased in both the SKM and BAT of the males and females. The differences between responses in male and female subjects further demonstrate the need for gender studies in the toxicology associated with drugs with abuse potential.