Brain Hyperthermia Is Induced by Methamphetamine and Exacerbated by Social Interaction

Abstract

Hyperthermia is a symptom of methamphetamine (METH) intoxication and a factor implicated in neurotoxicity during chronic METH use. To characterize the thermic response to METH, it was injected once daily into rats at increasing doses (0, 1, 3, and 9 mg/kg, s.c.) while brain [nucleus accumbens (NAcc), hippocampus] and body (deep temporal muscle) temperatures were continuously monitored. METH produced dose-dependent hyperthermia, with brain structures (especially the NAcc) showing a more rapid and pronounced temperature increase than the muscle. At the highest dose, brain and body temperatures increased 3.5-4.0°C above basal levels and remained elevated for 3-5 hr. Stressful and other high-activity situations such as interaction with a conspecific female are also known to induce a significant hyperthermic response in the rat. A combination of social interaction and METH administration was tested for additive effects. Male rats were exposed daily to a conspecific female for a total of 120 min, and METH was injected at the same doses 30 min after the initial contact with the female. An initial hyperthermic response (ϳ1.5°C) to social interaction was followed by a large and prolonged hyperthermic response (3.5-5.0°C, 5-7 hr at 9 mg/kg) to METH, which was again stronger in brain structures (especially in the NAcc) than in the muscle. Although the combined effect of the hyperthermic events was not additive, METH administration during social interaction produced stronger and longer-lasting increases in brain and body temperature than that induced by drug alone, heating the brain in some animals near its biological limit (Ͼ41°C).

MDMA (“ecstasy”), methamphetamine and their combination: long-term changes in social interaction and neurochemistry in the rat

“…Conversely, neither of the groups given only METH showed hyperthermia. Previous studies showing hyperthermia with METH in rats have used notably higher doses than those used here (Haughey et al 2000;Brown et al 2003).…”

Modeling Human Methamphetamine Exposure in Nonhuman Primates: Chronic Dosing in the Rhesus Macaque Leads to Behavioral and Physiological Abnormalities

“…One of our main goals was to prevent critical hyperthermia in naïve animals, not only as a safety issue, but also because it has been implicated as cause of METH-related neurotoxicity in acute high dose protocols (Xie et al, 2000;Riddle et al, 2002;Brown et al, 2003). One of the long-term goals of this work is to understand how METH-induced hyperther- Figure 3 Effect of METH on average total 24 h urinary cortisol excretion over the course of all three periods, Saline, METH Ramp-up, and METH Maintenance (mean7SEM).…”

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

“…These effects are modulated by social interaction and warm environments, but the pattern of modulation differs markedly from that produced by MDMA and methamphetamine (Brown et al, 2003;Kiyatkin, 2013;Kiyatkin et al, 2014). Although MDMA and methylone have similar potency as monoamine releasing agents (Baumann et al, 2012;Eshleman et al, 2013;Simmler et al, 2013) and both drugs induce moderate hyperthermic effects under quiet resting conditions, the MDMA-induced hyperthermia is greatly enhanced during social interaction and in warm environments (synergistic or supra-additive interaction) (Kiyatkin et al, 2014), whereas the effects of methylone do not show additive interaction.…”

“…Under these conditions, the decrease in Skin-Muscle differentials produced by methylone was delayed and smaller, suggesting weaker cutaneous vasoconstriction. Although atypical for MDMA and methamphetamine (Brown et al, 2003), this lack of potentiation suggests that methylone and social interaction share common effector mechanisms (eg, sympathetic activation) to induce brain hyperthermia. When these mechanisms are naturally activated during social interaction (ie, when rats are hyperactive, brain metabolic activity is increased and cutaneous vessels are physiologically constricted), the effects of the drug per se become weaker while the overall hyperthermic response does not change.…”