The relationship between hyperthermia and glycogenolysis in 3,4-methylenedioxymethamphetamine-induced serotonin depletion in rats
Introduction
3,4-methylenedioxymethamphetamine (MDMA), a ring-substituted amphetamine analog, is widely abused as a recreational drug, and there is concern that the drug may damage serotonergic nerve terminals [17]. MDMA-induced neurotoxicity of serotonergic nerve terminals in rodents and nonhuman primates is evidenced by several biochemical and immunocytochemical findings such as depletion of tissue concentration of serotonin (5-HT) and its major metabolite, 5-hydroxyindoleacetic acid [43], [51], decrease in the activity of the enzyme tryptophan hydroxylase [44], reduction in the [3H] paroxetine-labeled 5-HT reuptake sites [2], and reduced immunostaining of 5-HT terminals [38].
Although the exact mechanisms involved in the serotonergic neurotoxicity produced by amphetamine analogs are not completely known, evidence is supportive of a role of oxidative and/or bioenergetic stress in the process. For example, MDMA increases hydroxyl radical formation [11], [46], [47] and reduces the concentration of the endogenous antioxidants vitamin E and ascorbic acid [48]. The administration of antioxidants also has been shown to attenuate MDMA-induced 5-HT depletion [10], [18], [48]. The involvement of bioenergetic stress is predicated on the findings that methamphetamine reduces striatal concentration of ATP [9] and administration of energy substrates, i.e., ubiquinone and nicotinamide, attenuates methamphetamine-induced neurotoxicity [49]. In addition, MDMA produces a rapid and transient inhibition of mitochondrial function [8], and the mitochondrial toxin malonate greatly exacerbates MDMA neurotoxicity [35].
The findings that substituted amphetamines decrease brain glycogen [13], [19], [21] and increase the extracellular concentration of glucose in the brain [13] also are consistent with the view that amphetamines disrupt cellular energetics. MDMA has also been shown to activate glycogen phosphorylase, an enzyme responsible for the breakdown of glycogen, in astroglial-rich primary cultures [40].
Hyperthermia has been postulated to contribute to substituted amphetamine-induced neurotoxicity [7], [25], [26], and alterations in ambient temperature at which methamphetamine or MDMA are administered to rats affect the magnitude of neurotoxicity [3], [4], [5], [16], [27], [45]. Hyperthermia also may contribute to MDMA-induced glycogenolysis [13].
The purpose of the present study was to examine the relationship between MDMA-induced hyperthermia and glycogenolysis as it relates to the process of MDMA-induced serotonergic neurotoxicity.
Section snippets
Animal procedures
Male rats of Postnatal Day (PND)70 (300–325 g) and PND21 rats of the Sprague–Dawley strain (Charles River, Portage, MI) were used in the studies. The adult male (PND70) rats were housed three per cage in a temperature- (22–24 °C) and humidity-controlled room with a 12:12-h light–dark cycle and allowed food and water ad libitum. Pregnant rats (Charles River, Portage, MI) were singly housed, and upon parturition, the offspring in each litter were counted, sexed, and culled to eight pups (four
Results
A single injection of MDMA (20 mg/kg sc) produced a significant (t=7.1, P<0.001) increase in body temperature of 1.3 °C in PND21 rats maintained at 24 °C (Table 1). MDMA-induced hyperthermia in PND21 rats at 24 °C was accompanied by a significant (P<0.001) 34% decrease in glycogen content in the brain (Fig. 1A).
Maintenance of PND21 rats at a cool ambient temperature of 17 °C not only prevented MDMA-induced hyperthermia but also completely abolished the MDMA-induced glycogenolysis. Indeed, at 17
Discussion
Amphetamine analogs have been shown to produce a breakdown of brain glycogen in rodents. The systemic administration of amphetamine has been shown to deplete brain glycogen in mice [21] and rats [32], [37]. Parachloroamphetamine, MDMA, and methamphetamine also have been shown to produce glycogenolysis in the rat brain [13], [19]. In the present study, MDMA administration resulted in the depletion of brain glycogen in both PND21 and PND70 rats maintained at 24 °C, and these results are
Acknowledgements
This study was supported by the grant USPHS DA07427.
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