Studies on the role of dopamine in the degeneration of 5‐HT nerve endings in the brain of Dark Agouti rats following 3,4‐methylenedioxymethamphetamine (MDMA or ‘ecstasy’) administration

Abstract

1 We investigated whether dopamine plays a role in the neurodegeneration of 5-hydroxytryptamine (5-HT) nerve endings occurring in Dark Agouti rat brain after 3,4-methylenedioxymethamphetamine (MDMA or`ecstasy') administration. 2 Haloperidol (2 mg kg 71 i.p.) injected 5 min prior and 55 min post MDMA (15 mg kg 71 i.p.) abolished the acute MDMA-induced hyperthermia and attenuated the neurotoxic loss of 5-HT 7 days later. When the rectal temperature of MDMA+haloperidol treated rats was kept elevated, this protective e ect was marginal. 3 MDMA (15 mg kg 71 ) increased the dopamine concentration in the dialysate from a striatal microdialysis probe by 800%. L-DOPA (25 mg kg 71 i.p., plus benserazide, 6.25 mg kg 71 i.p.) injected 2 h after MDMA (15 mg kg 71 ) enhanced the increase in dopamine in the dialysate, but subsequent neurodegeneration was unaltered. L-DOPA (25 mg kg 71 ) injected before a sub-toxic dose of MDMA (5 mg kg 71 ) failed to induce neurodegeneration. 4 The MDMA-induced increase in free radical formation in the hippocampus (indicated by increased 2,3-and 2,5-dihydroxybenzoic acid in a microdialysis probe perfused with salicylic acid) was unaltered by L-DOPA. 5 The neuroprotective drug clomethiazole (50 mg kg 71 i.p.) did not in¯uence the MDMA-induced increase in extracellular dopamine. 6 These data suggest that previous observations on the protective e ect of haloperidol and potentiating e ect of L-DOPA on MDMA-induced neurodegeneration may have resulted from e ects on MDMA-induced hyperthermia. 7 The increased extracellular dopamine concentration following MDMA may result from e ects of MDMA on dopamine re-uptake, monoamine oxidase and 5-HT release rather than aǹ amphetamine-like' action on dopamine release, thus explaining why the drug does not induce degeneration of dopamine nerve endings.

The Pharmacology and Clinical Pharmacology of 3,4-Methylenedioxymethamphetamine (MDMA, “Ecstasy”)

“…3. Release and Depletion of Dopamine in the Brain. MDMA also rapidly increases dopamine release from cerebral tissue, as has been shown by both in vivo microdialysis (Yamamoto and Spanos, 1988;Gough et al, 1991;Nash and Brodkin, 1991;Nash and Yamamoto, 1992;Gudelsky et al, 1994;Yamamoto et al, 1995;Koch and Galloway, 1997;Sabol and Seiden, 1998;Colado et al, 1999a;Nixdorf et al, 2001) and by in vitro studies using tissue slices (Johnson et al, 1986;Schmidt, 1987b;Crespi et al, 1997). In vivo studies have generally found the striatal tissue concentration of dopamine to be raised and the metabolite concentration lowered in the first few hours after MDMA administration (Logan et al, 1988;Yamamoto and Spanos, 1988;Gough et al, 1991;Schmidt et al, 1991;Colado and Green, 1994).…”

“…Rather different conclusions on the role of dopamine in MDMA-induced neurotoxicity were reached by Colado et al (1999a) in their study. Like Shankaran et al (1999b) they also observed that MDMA increased extracellular dopamine concentrations in the striatum and they also showed that L-DOPA administration produced an enhancement in extracellular dopamine concentration.…”

“…The peak release occurred within 120 min after drug administration and returned toward baseline values within 180 min. Colado et al (1999a) administered MDMA to male Dark Agouti rats and, using in vivo microdialysis, demonstrated a rapid, significant increase in extracellular dopamine concentrations in the striatum, and a sustained depletion of DOPAC and HVA.…”

Elevation of Ambient Room Temperature has Differential Effects on MDMA-Induced 5-HT and Dopamine Release in Striatum and Nucleus Accumbens of Rats

“…Catechol and indole efflux in the brain in vivo was measured by the method described in detail by Colado et al (1999).…”

Pre-Exposure to (±)3,4-methylenedioxy-methamphetamine (MDMA) Facilitates Acquisition of Intravenous Cocaine Self-Administration in Rats

“…As noted in the introductory section, a large body of evidence indicates that repeated treatment with psychomotor stimulants sensitizes the mesolimbic DA system. MDMA also stimulates DA release (Kankaanpaa et al 1998) without any neurotoxic effect on DA neurons (O'Shea et al 1998;Colado et al 1999). Therefore, it is possible that for rats in the MDMA-20 group, repeated injection of MDMA sensitized the mesolimbic DA system by virtue of repeated release of DA.…”