Sympatho-adrenal involvement in methamphetamine-induced hyperthermia through skeletal muscle hypermetabolism
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.
Section snippets
Animals
Male Wistar rats weighing 300–350 g were used. The rats were housed in individual cages (40×25×25 cm) maintained at 26±1°C with a cycle of 12 h light (7:00 a.m.–7:00 p.m.) and 12 h dark. All procedures were reviewed by the committee of Ethics on Animal Experiment in Yamaguchi University School of Medicine and carried out according to the Guidelines for Animal Experiment in Yamaguchi University School of Medicine and Government legislation (Law No. 105 and Notification No. 6).
Measurement of body temperature and oxygen consumption
Body temperature
Results
Fig. 1 shows that the body temperature increased rapidly after injection of methamphetamine (1 mg/kg, i.p.), peaking at 50 min, and then gradually declined (panel A). The increase in oxygen consumption preceded that of body temperature with a peak at 10 min after the injection of methamphetamine followed by gradual decline (panel B).
To explore whether the increase in sympathetic outflow is a cause of the hyperthermia, we performed chemical sympathectomy by i.p. injection of 6-hydroxydopamine.
Discussion
The present study is the first to demonstrate the involvement of the sympatho-adrenal axis in methamphetamine-induced hyperthermia, which is caused by skeletal muscle hypermetabolism. This speculation is based on the observation that sympathectomy, adrenalectomy, and dantrolene treatment inhibited the hyperthermic effect of methamphetamine.
Since adrenal demedullation did not suppress methamphetamine-induced hyperthermia (Fig. 3), the suppression of the hyperthermia by 6-hydroxydopamine (Fig. 2)
Acknowledgements
We are grateful to Dr. Prof. Shoji Nakamura for critical reading of this manuscript and to Dr. Tomoki Nakamori for experimental support.
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2016, Autonomic Neuroscience: Basic and ClinicalCitation Excerpt :In support of this hypothesis is the finding that propranolol prevents methamphetamine-induced hyperthermia in laboratory mice (Albers and Sonsalla, 1995). Evidence for a peripheral effect includes the observation that methamphetamine-induced hyperthermia in laboratory rats is prevented by sympathectomy or adrenalectomy, which suggests that stimulant release of norepinephrine from sympathetic nerve terminals increases thermogenesis in skeletal muscles under the influence of glucocorticoids (Makisumi et al., 1998). Contributing mechanisms to ensuing hyperthermia may include activation of astrocytes and microglia, peripheral catecholamine release, increased skeletal muscle metabolism, tachycardia, hypertension, peripheral vasoconstriction, and cytokine formation and release (Matsumoto et al., 2014; Kiyatkin, 2013; Kiyatkin, 2005).