Evidence for the Involvement of Nitric Oxide in 3,4-Methylenedioxymethamphetamine-Induced Serotonin Depletion in the Rat Brain

Abstract

Production of reactive oxygen and/or nitrogen species has been thought to contribute to the long-term depletion of brain dopamine and serotonin (5-HT) produced by amphetamine derivatives, i.e., methamphetamine and 3,4-methylenedioxymethamphetamine (MDMA). In the present study, the effects of nitric-oxide synthase (NOS) inhibitors were examined on the long-term depletion of striatal dopamine and/or 5-HT produced by the local perfusion of malonate and MDMA or the systemic administration of MDMA. The effect of MDMA on nitric oxide formation and nitrotyrosine concentration also was determined. Perfusion with MDMA and malonate resulted in a 34% reduction of 5-HT and 49% reduction of dopamine concentrations in the striatum. The systemic administration of NOS inhibitors, N-nitro-L-arginine methyl ester hydrochloride and S-methyl-Lthiocitrulline (S-MTC), and the peroxynitrite decomposition catalyst Fe(III) tetrakis (1-methyl-4-pyridyl) porphyrin pentachloride attenuated the MDMA-and malonate-induced depletion of striatal dopamine and 5-HT. S-MTC also attenuated the depletion of 5-HT in the striatum produced by the systemic administration of MDMA without attenuating MDMA-induced hyperthermia. Additionally, the systemic administration of MDMA significantly increased the formation of nitric oxide and the nitrotyrosine concentration in the striatum. These results support the conclusion that MDMA produces reactive nitrogen species in the rat that contribute to the neurotoxicity of this amphetamine analog.

Molecular and Cellular Mechanisms of Ecstasy-Induced Neurotoxicity: An Overview

“…The authors postulated that MDMA depletes 5-HT by increasing tyrosine brain concentration, which can be converted to DA within 5-HT terminals [411]. Another study reported that MDMA (10 mg/kg×4, i.p., every 2 h) also promoted an elevation of extracellular tyrosine concentrations in the striatum of male Sprague-Dawley rats [412]. Posterior MAO metabolism of this monoamine would explain free radical formation inside the nerve terminal that would lead to degeneration.…”

Long‐lasting neuroprotective effect of sildenafil against 3,4‐methylenedioxymethamphetamine‐ induced 5‐hydroxytryptamine deficits in the rat brain

“…Thus, free radical scavengers and antioxidants attenuate MDMA-induced 5-HT deficits (for review see Capela et al, 2009;Puerta et al, 2009a), providing indirect evidence for the involvement of free radicals in the mechanism of MDMA neurotoxicity. In addition, MDMA has been reported to produce cellular changes, e.g., lipid peroxidation or protein nitration, consistent with the formation of free radicals (Sprague and Nichols, 1995;Colado et al, 1997;Darvesh et al, 2005). Finally, Colado et al (1997) and Shankaran et al (1999) demonstrated that MDMA increases the formation of 2,3-dihydroxybenzoic acid from salicylate in hippocampal and striatal dialysates, a conversion that occurs in the presence of a high concentration of free radicals, an effect reversed by ascorbic acid (Shankaran et al, 2001).…”

“…On the other hand, it has been shown that MDMA increases nitrotyrosine formation, which is a stable marker of peroxynitrite formation (Darvesh et al, 2005), a highly reactive anion formed in the reaction of nitric oxide (NO) with superoxide radicals (Ischiropoulos and al-Mehdi, 1995). Accordingly, we next studied the effects of sildenafil pretreatment on nitrotyrosine formation caused by MDMA (3 3 5 mg/kg i.p.).…”

Mechanisms of Action and Persistent Neuroplasticity by Drugs of Abuse

“…The importance of decreased ATP levels in amphetamine toxicity is demonstrated by an experiment where neural glucose uptake was prevented by administration of 2-deoxyglucose, a manipulation that enhanced both the decrease in ATP levels observed directly after METH treatment as well as the loss of striatal DA 1 week later (Chan et al, 1994). Similarly, inhibition of metabolism by directly interfering with the ETC also increases toxicity because the potent complex II inhibitor malonate exacerbated both METH and MDMA toxicity (Burrows et al, 2000;Darvesh et al, 2005), whereas application of the energy substrates decylubiquinone or nicotinamide 6 hours after METH treatment reduced toxicity (Stephans et al, 1998).…”