Oxidative stress has been demonstrated to occur in response to high doses of substituted amphetamines such as methamphetamine (METH) and 3,4-methlyene-dioxymethamphetamine (MDMA). This term represents a set of complex and multi-faceted precursor events that occur in both a parallel and serial manner, eventually converging to produce oxidative damage. This critical review goes beyond the compilation of previously well-documented evidence demonstrating that oxidative stress mediates METH and MDMA toxicity to dopamine and/or serotonin nerve terminals. The diverse causes, effects, and impact of pro-oxidative processes produced by these drugs are highlighted, integrated, and assembled into a proposed temporal sequence in an effort to explain the long-term neurochemical changes produced by amphetamines. Multiple factors are considered, including dopamine, glutamate, impaired mitochondrial bioenergetics, and inflammatory processes, all of which converge and are necessary but alone may be insufficient to cause damage to dopamine and/or 5-HT terminals. In addition, the processes linking inflammation and oxidative stress are considered and described as a feedforward process. The self-perpetuating cycle of inflammation and oxidative stress that is initiated by dopamine, glutamate, and mitochondrial dysfunction may extend well beyond the acute pharmacodynamic effects of the drugs and could represent an underlying and potentially progressive degenerative process.

The role of serotonin 5-HT 2 receptors (5-HT 2 R) in the hyperactivity induced by ( ϩ )-3,4-methylenedioxymethamphetamine (( ϩ )-MDMA; 3 mg/kg) was investigated. Hyperactivity induced by ( ϩ )-MDMA was robustly potentiated by the 5-HT 2B/2C R antagonist SB 206553 (1.0, 2.0, and 4.0 mg/kg). Administration of the 5-HT 1B/1D R antagonist GR 127935 (2.5 mg/kg) or the 5-HT 2A R antagonist M100907 (1.0 mg/kg) partially suppressed the potentiated hyperactivity seen following SB 206553 plus ( ϩ )-MDMA; a blockade to activity levels seen with ( ϩ )-MDMA alone was observed following the combination of GR 127935 plus M100907. A modest potentiative interaction was seen when SB 206553 was combined with the DA releaser amphetamine (0.5 mg/kg) or amphetamine plus the 5-HT releaser fenfluramine (4.0 mg/ kg). SB 206553 (1-4 mg/kg), GR 127935 (2.5 mg/kg) and M100907 (1 mg/kg) did not alter spontaneous activity upon administration singly or in combination. These data suggest that activation of 5-HT 2C R exerts a strong inhibitory influence on the hyperactivity induced by ( ϩ )- receptors; 5-HT 2A receptors; 5-HT 2C receptors; M100907; MDL 100907; MDMA; 3,4-Methylenedioxymethamphetamine; SB 206553; Serotonin 3,4-Methylenedioxymethamphetamine (MDMA; "ecstasy") is a commonly abused amphetamine derivative that evokes a unique set of stimulant, emotional and perceptual effects distinguishable from the parent drug amphetamine (Greer and Tolbert 1986). The mechanisms of action of both amphetamine and MDMA are based upon their ability to reverse monoamine reuptake transporters resulting in monoamine release from nerve terminals (Rudnick and Wall 1992). Amphetamine is selective for the release of dopamine (DA) via the DA reuptake transporter (Crespi et al. 1997), while MDMA has greater affinity for the serotonin (5-hydroxytryptamine; 5-HT) transporter (SERT) (Battaglia et al. 1988;Crespi et al. 1997). The ratio of 5-HT release to DA release is much greater for MDMA than for amphetamine (Crespi et al. 1997), although MDMA, like amphetamine, does release a larger amount of DA than 5-HT (Gudelsky and Nash 1996;White et al. 1994;Yamamoto and Spanos 1988). There are also similarities and stark contrasts when comparing the overt behaviors expressed upon the administration of these two drugs. Both drugs increase locomotor activity in rodents, but amphetamine-induced activity is amplified throughout the activity monitor, while MDMA-induced activity occurs predominantly in the periphery of the chamber (Callaway et al. 1990;. MDMA also produces aspects of the "5-HT syndrome" (Spanos and Yamamoto 1989) and decreased investigatory behavior . A large body of literature suggests that accumulation of DA in the synapse is a crucial mediator of the behavioral effects of psychostimulants such as amphetamine and cocaine (Kelly et al. 1975;Robledo et al. 1992). Dopamine antagonists (Kehne et al. 1996) and DA depletion with the DA neurotoxin 6-hydroxydopamine ) have been noted to attenuate the behavioral effects of MDMA. However, several lines of evidence ...

Acquisition of cocaine self-administration (0.125, 0.25 or 0.5 mg/kg/infusion) was assessed in rats that had received prior exposure to either saline or amphetamine (2.0 mg/kg). Acquisition of self-administration was dose-dependent, with the highest dose leading to the shortest latency to reliably discriminate between depression of a lever that resulted in drug delivery and an inactive lever. Latency to acquisition of the lever discrimination for rats that had received prior exposure to amphetamine was shorter than for the saline-pretreated counterparts in each cocaine dosage group. This suggests that repeated exposure to this drug prior to self-administration testing sensitized the rats to the reinforcing effects of cocaine. Co-administration of MK-801 (0.25 mg/kg, IP), a non-competitive NMDA antagonist, blocked the ability of chronic exposure to amphetamine to sensitize rats to cocaine. In experienced self-administering rats, acute pretreatment with MK-801 resulted in a loss of discriminative responding. The number of inactive lever responses was consistently higher than the number of active lever responses across all cocaine dosage groups. These data suggest that the NMDA receptor, possibly through interactions with dopamine systems, is critical for both the development and expression of sensitization to cocaine's reinforcing effects produced by intermittent preexposures to amphetamine.

3,4,-Methylenedioxymethamphetamine (MDMA; 'ecstasy') acts at monoamine nerve terminals to alter the release and re-uptake of dopamine and 5-HT. The present study used microdialysis in awake rats to measure MDMA-induced changes in extracellular GABA in the ventral tegmental area (VTA), simultaneous with measures of extracellular dopamine (DA) in the nucleus accumbens (NAC) shell. (+)-MDMA (0, 2.5, 5 and 10 mg/kg, i.p.) increased GABA efflux in the VTA with a bell-shaped dose-response. This increase was blocked by application of TTX through the VTA probe. MDMA (5 mg/kg) increased 5-HT efflux in VTA by 1037% (p < 0.05). The local perfusion of the 5-HT 2B/2C antagonist SB 206553 into the VTA reduced VTA GABA efflux after MDMA from a maximum of 229% to a maximum of 126% of basal values (p < 0.05), while having no effect on basal extracellular GABA concentrations. DA concentrations measured simultaneously in the NAC shell were increased from a maximum of 486% to 1320% (p < 0.05). The selective DA releaser d-amphetamine (AMPH) (4 mg/kg) also increased VTA GABA efflux (180%), did not alter 5-HT and increased NAC DA (875%) (p < 0.05), but the perfusion of SB 206553 into the VTA failed to alter these effects. These results suggest that MDMA-mediated increases in DA within the NAC shell are dampened by increases in VTA GABA subsequent to activation of 5-HT 2B/2C receptors in the VTA.

The specific mechanisms underlying (+)-3,4-methylenedioxymethamphetamine (MDMA)-induced damage to 5-HT terminals are unknown. Despite the hypothesized role for dopamine (DA) and DA-derived free radicals in mediating this damage, it remains unclear why MDMA produces long-term depletions of 5-HT in brain regions that are sparsely innervated by DA neurons. We hypothesized that the precursor to DA biosynthesis, tyrosine, mediates MDMA-induced 5-HT depletions. Extracellular tyrosine concentrations increased fivefold in striatum and 2.5-fold in hippocampus during the administration of neurotoxic doses of MDMA. In vitro results show that L-tyrosine can be hydroxylated nonenzymatically to the DA precursor l-3,4-dihydroxyphenylalanine (DOPA) under pro-oxidant conditions. The local infusion of L-tyrosine into the striatum or hippocampus during MDMA administration potentiated the acute increase in extracellular DA and the long-term depletion of 5-HT after MDMA. Coinfusion of the aromatic amino acid decarboxylase (AADC) inhibitor m-hydroxybenzylhydrazine attenuated these effects in hippocampus and decreased basal extracellular DA in the striatum. In contrast, the reverse dialysis of the tyrosine hydroxylase inhibitor alpha-methyl-p-tyrosine into the hippocampus did not affect MDMA-induced increases in extracellular DA or the long-term depletion in 5-HT. These results show that MDMA increases the concentration of tyrosine in the brain to cause a long-term depletion of 5-HT via the nonenzymatic, tyrosine hydroxylase-independent, hydroxylation of tyrosine to DOPA and subsequently to DA via AADC. Overall, the findings suggest that MDMA depletes 5-HT by increasing tyrosine and its eventual conversion to DA within 5-HT terminals.