Ascorbic acid prevents 3,4-methylenedioxymethamphetamine (MDMA)-induced hydroxyl radical formation and the behavioral and neurochemical consequences of the depletion of brain 5-HT

Actions of 3,4-methylenedioxymethamphetamine (MDMA) on cerebral dopaminergic, serotonergic and cholinergic neurons

“…It was demonstrated that the increase in the extracellular concentration of ACh in the PFC elicited by MDMA was attenuated in rats previously exposed to a neurotoxic regimen of MDMA in much the same manner as has been reported for the MDMA induced increase in 5-HT release (Shankaran and Gudelsky, 1999;Shankaran et al, 2001). In contrast, physical (i.e., tail pinch) or psychological (i.e., intruder rat) stressors evoked a similar increase in ACh release in the PFC of control animals and animals previously exposed to a neurotoxic regimen of MDMA (Nair and Gudelsky, 2006b).…”

“…Indeed, Gartside et al (1996) reported that treatment of rats with a high dose regimen of MDMA results in a reduction in 5-HT release evoked by electrical stimulation of the raphe nucleus. It also has been demonstrated that the ability of MDMA to increase extracellular concentrations of 5-HT is significantly diminished in rats previously exposed to a neurotoxic regimen of MDMA (Shankaran et al, 2001;Amato et al, 2007). It was further demonstrated by Shankaran et al (2001) that concomitant treatment of rats with ascorbic acid with a neurotoxic regimen of MDMA not only prevents MDMA induced depletion of brain 5-HT but also the loss in ability of MDMA to evoke 5-HT release.…”

“…It also has been demonstrated that the ability of MDMA to increase extracellular concentrations of 5-HT is significantly diminished in rats previously exposed to a neurotoxic regimen of MDMA (Shankaran et al, 2001;Amato et al, 2007). It was further demonstrated by Shankaran et al (2001) that concomitant treatment of rats with ascorbic acid with a neurotoxic regimen of MDMA not only prevents MDMA induced depletion of brain 5-HT but also the loss in ability of MDMA to evoke 5-HT release. This finding further supports the conclusion that MDMA-induced 5-HT neurotoxicity is accompanied by a reduction in the ability of pharmacological agents (e.g., MDMA) that are known 5-HT releasing agents to subsequently evoke 5-HT release in multiple brain regions.…”

“…However, following a neurotoxic regimen of MDMA, the ability of a subsequent injection of MDMA to elicit the 5-HT behavioral syndrome has been shown to be greatly diminished (Shankaran and Gudelsky, 1999;Shankaran et al, 2001). Series et al (1995) and Baumann et al (1998) also have demonstrated that the acute behavioral effects of fenfluramine are diminished following treatment with 5-HT depleting regimens of p-choloramphetamine, fenfluramine or MDMA.…”

Cellular and molecular mechanisms involved in the neurotoxicity of opioid and psychostimulant drugs

“…Hydroxyl radical formation was reported in the hippocampus and striatum of rats upon peripheral injection of MDMA (Shankaran et al, 2001), and was dependent on SERT activity (Shankaran et al, 1999). Furthermore, depletion of GSH upon MDMA exposure was observed in vitro in rat cortical neurons (Capela et al, 2007a) and in vivo in the mouse hippocampus, along with a decrease in Cu/Zn SOD activity (Frenzilli et al, 2007).…”