Prior Exposure to Chronic Stress and MDMA Potentiates Mesoaccumbens Dopamine Release Mediated by the 5-HT1B Receptor

Abstract

( + ) 3,4,-Methylenedioxymethamphetamine (MDMA) is an abused drug that acutely releases serotonin (5-HT) and dopamine (DA) but produces long-term damage to 5-HT terminals. MDMA-induced DA release has been shown to be dampened by 5-HT. Although stress also activates the mesolimbic DA pathway, it is unknown if chronic stress after exposure to neurotoxic doses of MDMA will augment MDMA-induced DA release in the nucleus accumbens shell (NAcc(sh)). Rats were pretreated with MDMA (10 mg/kg  4, intraperitoneal (i.p.)). After 7 days, rats were subjected to 10 days of chronic unpredictable stress. DA release in the NAcc(sh) and 5-HT in the ventral tegmental area (VTA) were measured after a challenge injection of MDMA (5 mg/kg, i.p.). The combination of pretreatment with MDMA + stress decreased basal concentrations of 5-HT in the VTA and DA in the NAcc(sh) and enhanced MDMAstimulated DA release in the NAcc(sh). Pretreatment with MDMA or stress alone blunted MDMA-induced 5-HT release in the VTA. The augmentation of MDMA-induced DA release in rats pretreated with MDMA + chronic stress was attenuated by perfusion of the 5-HT 1B antagonist, GR127935 into the VTA before the MDMA challenge injection. These results suggest that prior exposure to both MDMA and stress can produce a long-term augmentation in mesolimbic DA transmission and enhanced drug abuse vulnerability that is mediated, in part, by the 5-HT 1B receptor in the VTA. Neuropsychopharmacology (2007) 32, 946-954.

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

“…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.…”

“…Several investigators have demonstrated that MDMA produces a marked increase in the extracelllular concentration of DA in the n. accumbens (Cadoni et al, 2005;Kankaanpaa et al, 1998;Marona-Lweicka et al, 1996;Amato et al, 2007;O-Shea et al, 2005;Bankson and Yamamoto, 2004). As in the striatum, MDMA-induced DA release in the n. accumbens appears also to be modulated by 5-HT-GABA interactions.…”

“…Amato et al (2007) reported that rats treated with a neurotoxic regimen of MDMA followed by chronic unpredictable stress exhibit augmentation of the MDMA-induced increase in the extracellular concentration of 5-HT in the VTA and augmentation of DA responses in the n. accumbens. A role for 5-HT in the VTA in the sensitization of mesolimbic DA transmission was inferred from the finding that the local infusion of a 5-HT1B antagonist into the VTA blunted the sensitization of DA release in the n. accumbens of animals exposed to repeated MDMA treatments and chronic unpredictable stress (Amato et al, 2007).…”

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

“…Thioether MDMA metabolites may also induce oxidative stress in neurons (Capela et al, 2007b). In addition, since MDMA also induces dopamine release in rats (Amato et al, 2007), dopamine metabolism may also explain MDMAinduced oxidative stress.…”

Oxidative Stress and Drugs of Abuse: An Update

“…MDMA also induces dopamine release in rats [106], and, thus, dopamine metabolism may also explain MDMAinduced oxidative stress. In addition, hydroxyl radical formation was reported in the hippocampus and striatum of rats upon peripheral injection of MDMA [23], and was dependent on serotonin transporter (SERT) activity [107].…”