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.
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(-1) i.p.) injected 5 min prior and 55 min post MDMA (15 mg kg(-1) 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 effect was marginal. 3. MDMA (15 mg kg(-1)) increased the dopamine concentration in the dialysate from a striatal microdialysis probe by 800%. L-DOPA (25 mg kg(-1) i.p., plus benserazide, 6.25 mg kg(-1) i.p.) injected 2 h after MDMA (15 mg kg(-1)) enhanced the increase in dopamine in the dialysate, but subsequent neurodegeneration was unaltered. L-DOPA (25 mg kg(-1)) injected before a sub-toxic dose of MDMA (5 mg kg(-1)) 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(-1) i.p.) did not influence the MDMA-induced increase in extracellular dopamine. 6. These data suggest that previous observations on the protective effect of haloperidol and potentiating effect of L-DOPA on MDMA-induced neurodegeneration may have resulted from effects on MDMA-induced hyperthermia. 7. The increased extracellular dopamine concentration following MDMA may result from effects of MDMA on dopamine re-uptake, monoamine oxidase and 5-HT release rather than an 'amphetamine-like' action on dopamine release, thus explaining why the drug does not induce degeneration of dopamine nerve endings.
Colado
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Departamento de Farmacologia, Facultad de Medicina, Universidad Complutense, Madrid, Spain.
O'Shea
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Granados
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Esteban
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Martín
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Green
A R
AR
D000818:Animals; D001831:Body Temperature / Q000187:drug effects; D001921:Brain / Q000187:drug effects* / Q000378:metabolism; D004298:Dopamine / Q000502:physiology*; D005609:Free Radicals; D006220:Haloperidol / Q000494:pharmacology; D007980:Levodopa / Q000494:pharmacology; D008297:Male; D018817:N-Methyl-3,4-methylenedioxyamphetamine / Q000633:toxicity*; D019636:Neurodegenerative Diseases / Q000139:chemically induced*; D017374:Paroxetine / Q000378:metabolism; D051381:Rats; D012701:Serotonin / Q000032:analysis*
D005609:Free Radicals; D012701:Serotonin; D017374:Paroxetine; D007980:Levodopa; D006220:Haloperidol; D018817:N-Methyl-3,4-methylenedioxyamphetamine; D004298:Dopamine