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

Dopamine does not appear to cause the damage to serotonin nerve endings that occurs in the brain of Dark Agouti rats after MDMA (ecstasy) administration. The drug haloperidol prevented both the acute rise in body temperature and the long-term loss of serotonin when given around the time of MDMA, but this protection was minimal when body temperature was kept high. MDMA increased dopamine levels in the brain by 800%, but boosting dopamine further with L-DOPA did not worsen the nerve damage, nor did it make a low, non-toxic dose of MDMA become toxic. The findings suggest that earlier studies linking dopamine to MDMA's neurotoxicity may have been confounded by effects on body temperature.

Study at a glance

Abstract

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. 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. 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. 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. The neuroprotective drug clomethiazole (50 mg kg −1 i.p.) did not influence the MDMA‐induced increase in extracellular dopamine. 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. 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. British Journal of Pharmacology (1999) 126 , 911–924; doi: 10.1038/sj.bjp.0702373