Summary
Acting as a substrate at the serotonin (5-HT) transporter, (+)-MDMA (3,4-methylenedioxymethamphetamine), is a potent releaser of 5-HT and causes toxicity to 5-HT neurons after repeated exposure. (+)-MDMA also releases dopamine (DA), although with less potency. Since we have shown previously that the intrastriatal application of 5-HT facilitates DA release, it was hypothesized that increased release of striatal 5-HT after MDMA may influence extracellular levels of DA. Using microdiaiysis in vivo, we found that (+)-MDMA (4.7 μmol/kg, i.v.) administration increased extracellular striatal DA levels to 501% of control (p < 0.01, n=12). However, in the presence of fluoxetine (14.4 μmol/kg, s.c.), which prevents (+)-MDMA effects on 5-HT release, the (+)-MDMA-induced increase in DA was significantly less (to 375% of control, p < 0.05, vs. no fluoxetine, n=8). In vitro studies with striatal slices, to test drug selectivity, showed that (+)-MDMA (0.3-3 μM) increased extracellular levels of both DA and 5-HT in a dose-dependent manner. Fluoxetine (3 μM) completely blocked the effects of (+)-MDMA on 5-HT release, but did not alter (+)-MDMA-induced DA release in vitro. The selective DA transport inhibitor GBR-12909 (1 μM), blocked (+)-MDMA's effect on DA release. It is concluded that 5-HT release after (+)-MDMA treatment partially contributes to (+)-MDMA's effect on DA release in vivo.
Article PDF
Similar content being viewed by others
Avoid common mistakes on your manuscript.
References
Battaglia G, Sharkey J, Kuhar MJ, De Souza EB (1991) Neuroanatomic specificity and time course of alterations in rat brain serotonergic pathways induced by MDMA (3,4-methylenedioxymethamphetamine): assessment using quantitative autoradiography. Synapse 8: 249–260
Bel N, Artigas F (1992) Fluvoxamine preferentially increases extracellular 5-hydroxytryptamine in the raphe nuclei: an in vivo microdialysis study. Eur J Pharmacol 229: 101–103
Benloucif SB, Galloway MP (1991) Facilitation of dopamine release in vivo by serotonin agonists: studies with microdialysis. Eur J Pharmacol 200: 1–8
Benloucif SB, Keegan MJ, Galloway MP (1993) Serotonin-facilitated dopamine release in vivo: pharmacological characterization. J Pharmacol Exp Ther 265: 373–377
Bradberry CW (1994) Microdialysis assessment of the impact of (+)3,4-methylenedioxymethamphetamine, cocaine, and cocaethylene on serotonergic neurons. Drug Dev Res 33: 1–9
Brodkin J, Malyala A, Nash JF (1993) Effect of acute monoamine depletion on 3,4-methylenedioxymethamphetamine-induced neurotoxicity. Pharmacol Biochem Behav 45: 647–653
Cass WC, Gerhardt GA (1994) Direct in vivo evidence that D2 receptors can modulate dopamine uptake. Neurosci Lett 176: 259–263
Chen J, Paredes W, Van Praag HM, Lowinson JH, Gardner EL (1992) Presynaptic dopamine release is enhanced by 5-HT3 receptor activation in medial prefrontal cortex of freely moving rats. Synapse 10: 264–266
Clark D, Salah RS, Galloway MP (1991) Differential agonist profile of the enantiomers of 3-PPP at striatal dopamine autoreceptors: dependence on extracellular dopamine. Synapse 8: 169–176
Galloway MP (1996) Augmentation of selective serotonin reuptake inhibitor antidepressant efficacy with pindolol and the relevance of 5-HT1A autoreceptors. Anxiety 2: 149–152
Galloway MP, Wolf ME, Roth RH (1986) Regulation of dopamine synthesis in the medial prefrontal cortex is mediated by release modulating autoreceptors: studies in vivo. J Pharmacol Exp Ther 236: 689–698
Galloway MP, Suchowski CS, Keegan MJ, Hjorth S (1993) Local infusion of the selective 5-HT-lb agonist CP-93,129 facilitates striatal dopamine release in vivo. Synapse 15: 90–92
Gough B, Ali SF, Slikker Jr W, Hoson RR (1991) Acute effects of 3,4-methylenedioxymethamphetamine (MDMA) on monoamines in rat caudate. Pharmacol Biochem Behav 39: 619–623
Hekmatpanah CR, Peroutka SJ (1990) 5-Hydroxytryptamine uptake blockers attenuate the 5-hydroxytryptamine-releasing effect of 3,4-methylenedioxy-methamphetamine and related agents. Eur J Pharmacol 177: 95–98
Hiramatsu M, Cho AK (1990) Enantiomeric differences in the effects of 3,4-methylenedioxymethamphetamine on extracellular monoamines and metabolites in the striaturn of freely-moving rats: an in vivo microdialysis study. Neuropharmacology 29: 269–275
Huang X, Nichols DE (1993) 5-HT2 receptor-mediated potentiation of dopamine synthesis and central serotonergic deficits. Eur J Pharmacol 238: 291–296
Iyer RN, Bradberry CW (1996) Serotonin-mediated increase in prefrontal cortex dopamine release: pharmacological characterization. J Pharmacol Exp Ther 277: 40–47
Malagie I, Trillat A-C, Jacquot C, Gardier AM (1995) Effects of acute fluoxetine on extracellular serotonin levels in the raphe: an in vivo microdialysis study. Eur J Pharmacol 286: 213–217
McCann UD, Ricaurte GA (1993) Reinforcing subjective effects of (+/−)3,4-methylenedioxymethamphetamine (“ecstasy”) may be separable from its neurotoxic actions: clinical evidence. J Clin Psychopharmacol 13: 214–217
McKenna DJ, Peroutka J (1990) Neurochemistry and neurotoxicity of 3,4-methylenedioxymethamphetamine (MDMA, “Ecstasy”). J Neurochem 54: 14–22
Meiergerd SM, Patterson TA, Schenk JO (1993) D2 receptors may modulate the function of striatal transporter for dopamine: kinetic evidence from studies in vitro and in vivo. J Neurochem 61: 764–767
Molliver ME, Berger UV, Mamounas LA, Molliver DC, O'Hearn E, Wilson MA (1990) Neurotoxicity of MDMA and related compounds: anatomic studies. Ann NY Acad Sci 600: 640–661
Nash JF (1990) Ketanserin pretreatment attenuates MDMA-induced dopamine release in the striatum as measured by in vivo microdialysis. Life Sci 47: 2401–2408
Nash JF, Yamamoto BK (1992) Methamphetamine neurotoxicity and striatal glutamate release: comparison to 3,4-methylenedioxymeth-amphetamine. Brain Res 581: 237–243
Nash JF, Meltzer HY, Gudelsky GA (1990) Effects of 3,4-methylenedioxymethamphetamine on 3,4-dihydroxyphenylalanine accumulation in the striatum and nucleus accumbens. J Neurochem 54: 1062–1067
Parsons LH, Justice JB Jr (1993) Perfusate serotonin increases extracellular dopamine in the nuceus accumbens as measured by in vivo microdialysis. Brain Res 606: 195–199
Parsons LH, Schad CA, Justice JB Jr (1993) Co-administration of the D2 antagonist pimozide inhibits up-regulation of dopamine release and uptake induced by repeated cocaine. J Neurochem 60: 376–379
Paxinos G, Watson C (1986) The rat brain in stereotaxic coordinates. Academic Press, New York
Peroutka SJ (1987) Incidence of recreational use of 3,4-methylenedioxymethamphetamine (MDMA; “Ecstasy”) on an undergraduate campus. N Engl J Med 317: 1542–1543
Peroutka SJ, Newman H, Harris H (1988) Subjective effects of 3,4-methylenedioxymethamphetamine in recreational users. Neuropsychopharm 1: 273–277
Ricaurte GA (1989) Studies of MDMA-induced neurotoxicity in nonhuman primates: a basis for evaluating long-term effects in humans. NIDA Res Monogr 94: 306–322
Ricaurte GA, DeLanney LE, Irwin I, Langston JW (1988) Toxic effects of MDMA on central serotonergic neurons in the primate: importance of route and frequency of drug administration. Brain Res 446: 165–168
Ricaurte GA, Martello AL, Katz JL, Martello MB (1992) Lasting effects of (±)-3,4-methylendioxymethamphetamine (MDMA) on central serotonergic neurons in nonhuman primates: neurochemical observations. J Pharmacol Exp Ther 261: 616–622
Robinson TE, Whishaw IQ (1988) Normalization of extracellular dopamine in striatum following recovery from a partial unilateral 6-OHDA lesion of the substantia nigra: a microdialysis study in freely moving rats. Brain Res 450: 209–224
Rudnick G, Wall SC (1991) The molecular mechanism of “ecstasy” [3,4-methylenedioxymethamphetamine (MDMA)]: serotonin transporters are targets for MDMA-induced sertotonin release. Proc Natl Acad Sci 89: 1817–1821
Rutter JJ, Auerbach SB (1993) Acute uptake inhibition increases extracellular serotonin in the rat forebrain. J Pharmacol Exp Ther 265: 1319–1324
Schmidt CJ, Taylor VL (1988) Direct central effects of acute methylenedioxymetham-phetamine on serotonergic neurons. Eur J Pharmacol 156: 121–131
Schmidt CJ, Taylor VL (1990) Reversal of the acute effects of 3,4-methylenedioxyme-thamphetamine by 5-HT uptake inhititors. Eur J Pharmacol 181: 133–136
Schmidt CJ, Abbate GM, Black CK, Taylor VL (1990a) Selective 5-hydroxytryptamine2 receptor antagonists protect against the neurotoxicity of methylenedioxymethamphetamine in rats. J Pharmacol Exp Ther 255: 478–483
Schmidt CJ, Taylor VL, Abbate GM, Nieduzak TR (1990b) 5-HT2 antagonists stereoselectively prevent the neurotoxicity of 3,4-metnylenedioxymethamphetamine by blocking the acute stimulation of dopamine synthesis: reversal by L-dopa. J Pharmacol Exp Ther 256: 230–235
Schmidt CJ, Fadayel GM, Sullivan CK, Taylor VL (1992) 5-HT2 receptors exert a statedependent regulation of dopaminergic function: studies with MDL 100,907 and the amphetamine analogue, 3,4-methylenedioxymethamphetamine. Eur J Pharmacol 223: 65–74
Stone DM, Merchant KM, Hanson GR, Gibb JVV (1987) Immediate and long-term effects of 3,4-methylenedioxymeth-amphetamine on serotonin pathways in the brain of rat. Neuropharmacology 26: 1677–1683
Stone DM, Johnson M, Hanson GR, Gibb JW (1988) Role of endogenous dopamine in the central serotonergic deficits induced by 3,4-methylenedioxymethamphetame. J Pharmacol Exp Ther 247: 79–87
Tanda G, Bassareo V, Di Chiara G (1996) Mianserin markedly and selectively increases extracellular dopamine in the prefrontal cortex as compared to the nucleus accumbens of the rat. Psychopharmacol 123: 127–130
Ugedo L, Grenhoff J, Svensson TH (1989) Ritanserin, a 5-HT2 receptor antagonist, activates midbrain dopamine neurons by blocking serotonergic inhibition. Psychopharmacol 98: 45–50
West AR, Galloway MP (1996) Regulation of serotonin-facilitated dopamine release in vivo: the role of protein kinase A activating transduction mechanisms. Synapse 23: 20–27
Yadid G, Cak K, Kopin U, Goldstein DS (1994) Endogenous serotonin stimulates striatal dopamine release in conscious rats. J Pharmacol Exp Ther 270: 1158–1165
Yamamoto BK, Spanos LJ (1988) The acute effects of methylenedioxymethamphetamine on dopamine release in the awake-behaving rat. Eur J Pharmacol 148: 195–203
Author information
Authors and Affiliations
Rights and permissions
About this article
Cite this article
Koch, S., Galloway, M.P. MDMA induced dopamine release in vivo: role of endogenous serotonin. J. Neural Transmission 104, 135–146 (1997). https://doi.org/10.1007/BF01273176
Received:
Accepted:
Issue Date:
DOI: https://doi.org/10.1007/BF01273176