Sympatho-adrenal involvement in methamphetamine-induced hyperthermia through skeletal muscle hypermetabolism

Abstract

We investigated the involvement of the sympatho-adrenal axis in the hyperthermia induced by methamphetamine by using a biotelemetric system. The intraperitoneal injection of methamphetamine (1 mg/kg) induced hyperthermia preceded by an increase in oxygen consumption in freely moving rats. The hyperthermic effect of methamphetamine was completely blocked by chemical sympathectomy with 6-hydroxydopamine (50 mg/kg, i.p.). Adrenalectomy, but not adrenal demedullation, prevented the hyperthermia. In adrenalectomized rats, dexamethasone supplementation (0.5 mg/kg, s.c.) restored the methamphetamine-induced hyperthermia. Furthermore, dantrolene (1 or 2 mg/kg, i.v.), which blocks Ca²⁺ release from the sarcoplasmic reticulum in skeletal muscle, attenuated the hyperthermia. These results suggest that methamphetamine stimulates norepinephrine release from sympathetic nerve terminals, which then enhances thermogenesis in skeletal muscle under the permissive action of glucocorticoids.

Introduction

Amphetamines have powerful stimulatory actions on the central and peripheral nervous systems and induce hypertension, hyperthermia, and various metabolic derangements (Callaway and Clark, 1994). Amphetamine abuse is a serious social problem, and many abusers have been reported to die as a result of hyperthermia (Askew, 1962; Clark et al., 1967; Zalis et al., 1967). However, the mechanism underlying the hyperthermia induced by methamphetamine is still unknown.

It has not been clarified whether amphetamines induce hyperthermia by acting on the central or the peripheral nervous system. As for the central mechanism, it has been proposed that activation of dopaminergic or serotonergic neurotransmission contributes to hyperthermia (Matsumoto and Griffin, 1971; Frey, 1975; Lin, 1979; Cox et al., 1981; Yamawaki et al., 1983; Gordon et al., 1991). Amphetamine also acts on the preoptic hypothalamic area (Lin et al., 1980). In support of the peripheral mechanism, it has been reported that amphetamine increases core temperature in unrestrained and curarized rats (Borbely et al., 1974) and that it increases the metabolism of brown adipose tissue and induces vasoconstriction through sympathetic activation (Bukowiecki et al., 1982; Astrup et al., 1985; Blaak et al., 1993). However, there have been no experimental studies of skeletal muscle thermogenesis after the administration of amphetamines.

Stress activates the hypothalamo-pituitary-adrenal axis and often occurs in association with amphetamine poisoning. In support of the role of stress, it has been reported that the behavioral and cardiovascular responses elicited by amphetamine administration are influenced by various stressors (Antelman et al., 1980). Additionally, amphetamines elevate the plasma concentration of catecholamines and corticosterone (Knych and Eisenberg, 1979; Vogel et al., 1984). Furthermore, it has been shown that sympathetic blockade or adrenalectomy attenuates the behavioral and cardiovascular responses to amphetamine administration (Faunt and Crocker, 1988; Rivet et al., 1989; Maccari et al., 1990; Deroche et al., 1992; Cador et al., 1993; Pauly et al., 1993; Badiani et al., 1995; Johnson et al., 1995). However, there is no report that amphetamines induce hyperthermia through activation of the sympatho-adrenal axis. To examine the latter possibility, it is mandatory to minimize the stress evoked by experimental manipulations. To overcome this difficulty, we used a biotelemetric system to show that the administration of methamphetamine either centrally or peripherally induces cardiovascular, thermal and behavioral responses, and sensitization in freely moving rats (Yoshida et al., 1993). We have also found that the cardiovascular responses elicited by methamphetamine injection are augmented by psychological stress (Makisumi et al., 1995).

In the present study, we focused on the involvement of the sympatho-adrenal system in the hyperthermia induced by methamphetamine by using a biotelemetric system. By means of chemical sympathectomy and adrenalectomy, we found that activation of the sympathetic nervous system and the permissive action of the glucocorticoids are involved in the hyperthermia caused by methamphetamine as a result of hypermetabolism in skeletal muscle.