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

Abstract

Oxidative and/or bioenergetic stress is thought to contribute to the mechanism of neurotoxicity of amphetamine derivatives, e.g., 3,4-methylenedioxymethamphetamine (MDMA). In the present study, the effect of MDMA on brain energy regulation was investigated by examining the effect of MDMA on brain glycogen and glucose. A single injection of MDMA (10 -40 mg/kg, s.c.) produced a dose-dependent decrease (40%) in brain glycogen, which persisted for at least 1 h. MDMA (10 and 40 mg/kg, s.c.) also produced a significant and sustained increase in the extracellular concentration of glucose in the striatum. Subjecting rats to a cool ambient temperature of 17°C significantly attenuated MDMA-induced hyperthermia and glycogenolysis. MDMAinduced glycogenolysis also was prevented by treatment of rats with the 5-hydroxytryptamine 2 (5-HT 2 ) antagonists 6-methyl-1-(1-methylethyl)-ergoline-8␤-carboxylic acid 2-hydroxy-1 methylprophyl ester maleate (LY-53,857; 3 mg/kg i.p.), desipramine (10 mg/kg i.p.), and iprindole (10 mg/kg i.p.). LY-53,857 also attenuated the MDMA-induced increase in the extracellular concentration of glucose as well as MDMA-induced hyperthermia. Amphetamine analogs (e.g., methamphetamine and parachloroamphetamine) that produce hyperthermia also produced glycogenolysis, whereas fenfluramine, which does not produce hyperthermia, did not alter brain glycogen content. These results support the conclusion that MDMA induces glycogenolysis and that the process involves 5-HT 2 receptor activation. These results are supportive of the view that MDMA promotes energy dysregulation and that hyperthermia may play an important role in MDMA-induced alterations in cellular energetics.

Serotonin-induced brain glycogenolysis in rainbow trout (Oncorhynchus mykiss)

“…In theory, these results are consistent with findings in mammals, in which it has been found that 5-HT2 receptors mediate the glycogenolytic action of 5-HT (Darvesh et al, 2002;Darvesh and Gudelsky, 2003). Administration of the generic agonist 5-HT2 (-m-5-HT) or the agonists 5HT2A/2C [(±)-DOI] or 5-HT2B/2C (m-CPP) produced glycogenolytic responses, of which that induced by the agonist 5-HT2B/2C was similar to that induced by the generic agonist (-m-5-HT) whereas that induced by the agonist 5-HT2A/2C was clearly of lower magnitude.…”

“…In mammals, the pharmacology of 5-HT modulation of brain glycogenolysis appears to involve different 5HT2 receptor subtypes (Xiaohu et al, 1993;Chen et al, 1995;Poblete and Azmitia, 1995;Darvesh et al, 2002;Darvesh and Gudelsky, 2003). It is known that, in the mammalian brain, glycogen is mainly stored in the astrocytes (Brown and Ransom, 2007) and that these cells express most of the 5-HT subtype receptors (Hirst et al, 1997;Porter and McCarthy, 1997;Hirst et al, 1998;Hanssonp and Ronnback, 2004;Li et al, 2008;Osredkar and Krzan, 2009), with the 5-HT1B and 5-HT2A subtypes being most widely distributed in the brain (Osredkar and Krzan, 2009).…”

Increased Anxiety 3 Months after Brief Exposure to MDMA (‘Ecstasy’) in Rats: Association with Altered 5-HT Transporter and Receptor Density

“…Other useful avenues of enquiry could examine changes in the efficacy of 5-HT receptor subtypes, changes in the transcription of 5-HT-related receptors, and alterations of basal and stimulated 5-HT within the synapse. The ability of MDMA to alter endocrine function chronically (Forsling et al, 2002) is another avenue through which anxiety may be affected as well as global effects on brain energy metabolism (Darvesh et al, 2002). Thus, it would be premature to conclude that the present study has isolated the mechanism through which MDMA chronically increases anxiety in rats.…”

The Pharmacology and Clinical Pharmacology of 3,4-Methylenedioxymethamphetamine (MDMA, “Ecstasy”)

“…MDMA resulted in an increase in glucose utilization in many brain regions, particularly areas concerned with the motor system, together with decreases in blood flow in regions such as the limbic and primary sensory nuclei, thereby indicating an uncoupling of blood flow from metabolic demand. Darvesh et al (2002) found that the glucose concentration increased following MDMA administration and demonstrated that this increase was linked to an increase in glycogenolysis, which in turn appeared to be linked to the MDMA-induced hyperthermia. The authors speculated that the altered cellular bioenergetics might be associated with the oxidative stress and subsequent neurotoxicity.…”