Protection against 3,4‐methylenedioxymethamphetamine‐induced neurodegeneration produced by glutathione depletion in rats is mediated by attenuation of hyperthermia

Abstract

3,4-Methylenedioxymethamphetamine (MDMA) administration produces neurotoxic degeneration of serotonin terminals in rat brain. These effects occur only after systemic administration and not after central injection, suggesting that peripheral metabolism, possibly hepatic, is required for toxicity. Glutathione is one of the principal cellular defence mechanisms, but conjugation with glutathione can, on some occasions, increase the reactivity of certain molecules. Previous studies have shown that central administration of glutathione adducts of a MDMA metabolite produces a neurotoxicity profile similar to that of systemic MDMA. In the present study, depletion of peripheral (hepatic) glutathione by 43% with DL-buthionine-(S,R)-sulfoximine (an inhibitor of glutathione synthesis) did not attenuate MDMA-induced neurotoxicity as indicated by the 34% loss of [ 3 H]paroxetine binding to the serotonin uptake sites in Dark Agouti rats treated with the inhibitor. However, a more profound depletion (92%) of glutathione by diethylmaleate (direct conjugation) administration significantly reduced the serotonergic neurotoxicity produced by MDMA. This depletion protocol also attenuated the hyperthermic response to MDMA. A combination protocol utilising both buthionine-(S,R)-sulfoximine and diethylmaleate that did not alter the hyperthermic response of the rats given MDMA also failed to attenuate the neurotoxicity. These findings indicate that glutathione depletion does not offer specific protection against MDMA-induced serotonin neurotoxicity in Dark Agouti rats.

Mephedrone, an abused psychoactive component of ‘bath salts’ and methamphetamine congener, does not cause neurotoxicity to dopamine nerve endings of the striatum

“…This is an interesting possibility that requires more investigation because MDMA can also cause damage to DA nerve endings of the striatum (Yamamoto and Bankson 2005, Steele et al 1994, Green et al 2003, Cadet et al 2007), it causes hyperthermia (Vorhees et al 2010, Sprague et al 2003, O'Shea et al 2002) and it also increases glial activation (Thomas et al 2004a, Torres et al 2010, Orio et al 2009, O'Callaghan and Miller 1994, Pu et al 1996). It is known that rats are more sensitive than mice to 5-HT nerve ending damage after treatment with METH or MDMA but it is clear that mice, like humans, readily show DA neuronal deficits after intoxication with the substituted amphetamines or cathinone derivatives (Fleckenstein et al 2007, Yamamoto et al 2010, Cadet et al 2007, Fleckenstein et al 2000).…”

Mice Lacking Multidrug Resistance Protein 1a Show Altered Dopaminergic Responses to Methylenedioxymethamphetamine (MDMA) in Striatum

“…In rats and monkeys, MDMA is selectively neurotoxic to serotonergic terminals; however, in mice, MDMA depletion of dopaminergic terminals predominates (O’Shea et al, 2002; Green et al, 2003; Colado et al, 2004; Quinton and Yamamoto, 2006; Baumann et al, 2007; Capela et al, 2009). MDR1a appears to facilitate entry of MDMA into brain, with mice lacking MDR1a protein being more resistant to MDMA-induced reductions in DA and DAT expression in brain (Mann et al, 1997).…”

The relationship between core body temperature and 3,4-methylenedioxymethamphetamine metabolism in rats: implications for neurotoxicity

“…Small changes in ambient temperature cause large changes in both core body temperature and MDMA-induced 5-HT neurotoxicity in the rat (Schmidt et al 1990;Malberg and Seiden 1998). Additionally, a common feature of many drugs known to prevent MDMA toxicity relies on their ability to block the acute hyperthermia induced by MDMA, with such protection disappearing if the temperature of rats is kept elevated (Che et al 1995;Farfel and Seiden 1995;Malberg et al 1996;Taraska and Finnegan 1997;Colado et al 1998;Colado et al 1999;Hervias et al 2000;O'Shea et al 2002;Morley et al 2004). Other nonpharmacological manipulations capable of preventing the acute hyperthermic response caused by MDMA also provide substantial protection against the neurotoxic effects of the drug (Sprague et al 2003).…”