Effects of Amphetamine on Protein Synthesis and Energy Metabolism in Mouse Brain: Role of Drug‐Induced Hyperthermia

Abstract

Changes in brain protein synthesis activity, and in brain levels of glucose, glycogen, and several high-energy phosphate metabolites, were evaluated under conditions of amphetamine-induced hyperthermia in mice. Protein synthesis showed a striking dependence on rectal temperature (TR), falling abruptly at TR above 40 degrees C. A similar result was obtained following direct heating of the animals. Protein synthesis activity in liver showed the same temperature dependence observed for brain. Increased synthesis of a protein with characteristics of the major mammalian stress protein, hsp 70, was demonstrated in both brain and liver following amphetamine administration. Brain protein synthesis showed significant recovery within 2 h after amphetamine administration whereas that of liver remained below 30% of control activity, suggesting significant temporal and quantitative differences in the response of individual tissues to elevated temperatures. Brain glycogen levels after amphetamine administration were significantly lower under conditions of ambient temperature which resulted in more severe drug-induced hyperthermia but did not correlate as strikingly as protein synthesis with the temperatures of individual animals. Brain glycogen also fell in animals whose temperatures were increased by brief exposure at high ambient temperature. Brain glucose levels did not consistently change with hyperthermia. Slight decreases in high-energy phosphates with increasing TR were likely the result of fixation artifact. These results demonstrate the fundamental role of hyperthermia in the reduction of protein synthesis in brain and other tissues by amphetamine, and suggest that temperature also constitutes a significant source of variability in the effects of this drug on brain energy metabolism, in particular glycogenolysis.

3,4-Methylenedioxymethamphetamine Produces Glycogenolysis and Increases the Extracellular Concentration of Glucose in the Rat Brain

“…In further support of this view is the present finding that maintenance of rats at a modestly cool ambient temperature (i.e., 17°C) prevented not only MDMA-induced glycogenolysis but also MDMA-induced hyperthermia. This finding is in agreement with the work of Nowak (1988), who reported that amphetamine-induced hyperthermia and glycogenolysis were less at 17 than at 27°C. Also consistent with a role of hyperthermia in the MDMA-induced alteration in energy regulation is the finding that the administration of MDMA via reverse dialysis into the striatum did not alter the extracellular concentration of glucose, whereas a significant increase was observed following the systemic administration of MDMA.…”

“…The induction of glycogen breakdown elicited by MDMA is consistent with the effects of other amphetamine analogs on brain glycogen content. Both PCA and d-amphetamine have been reported to reduce brain glycogen content (Nahorski and Rogers, 1975;Nowak, 1988;Heuther et al, 1997). Poblete and Azmitia (1995) have reported that under in vitro conditions MDMA increases the activity of glycogen phosphorylase, the enzyme responsible for the breakdown of glycogen.…”

The Role of Mitochondrial Uncoupling in 3,4-Methylenedioxymethamphetamine-Mediated Skeletal Muscle Hyperthermia and Rhabdomyolysis

“…Similar effects on glycogen content have also been noted in studies with d-amphetamine and other amphetamine analogs (Nahorski and Rogers, 1973;Nowak, 1988). Although these prior studies implicate an effect of stimulants on energy production in the brain, recent work has also shown a role for skeletal muscle in MDMA-mediated hyperthermia .…”

Inhibition of HSP70 Expression by Calcium Ionophore A23187 in Human Cells

“…In mammalian cells, HSP expression is induced in vivo in mammalian brain and other organs during hyperthermia (51), ischemia (52), and exposure to neurotoxin (53). Abnormal expression of HSPs has been described in a variety of pathophysiological states, which include fever, inflammation, oxidant injury, viral infection, and cancer (54), and a cytoprotective role of HSPs and HSP70 in particular has been shown in several pathological conditions, including ischemia (55) and virus infection (6,56).…”