Persistent cerebrovascular effects of MDMA and acute responses to the drug

A single dose of MDMA causes long-term loss of serotonin nerve terminals and disrupts the normal coupling between brain blood flow and glucose use. Three weeks after MDMA pretreatment in rats, serotonin transporter density fell by about 46% and paroxetine binding by 47%. Brain glucose use decreased widely, but blood flow did not change, indicating lost cerebrovascular constrictor tone. A subsequent MDMA dose increased glucose use but decreased blood flow overall; in half of pretreated rats, random focal hyperemia suggested a failure of autoregulation during MDMA-induced hypertension. The findings suggest that prior MDMA exposure does not protect against acute cerebrovascular dysfunction and may, in some individuals, increase stroke risk.

Study at a glance

Abstract

Abstract Acutely, 3,4,‐methylenedioxymethamphetamine (MDMA) induces cerebrovascular dysfunction [ Quate et al ., (2004) Psychopharmacol. , 173 , 287–295]. In the longer term the same single dose results in depletion of 5‐hydroxytrptamine (5‐HT) nerve terminals. In this study we examined the cerebrovascular consequences of this persistent neurodegeneration, and the acute effects of subsequent MDMA exposure, upon the relationship that normally exists between local cerebral blood flow (LCBF) and local cerebral glucose utilization (LCMRglu). Dark agouti (DA) rats were pre‐treated with 15 mg/kg i.p. MDMA or saline. Three weeks later, rats from each pre‐treatment group were treated with an acute dose of MDMA (15 mg/kg i.p.) or saline. Quantitative autoradiographic imaging was used to measure LCBF or LCMRglu with [ 14 C]‐iodoantipyrine and [ 14 C]‐2‐deoxyglucose, respectively. Serotonergic terminal depletion was assessed using radioligand binding with [ 3 H]‐paroxetine and immunohistochemistry. Three weeks after MDMA pre‐treatment there were significant reductions in densities of 5‐HT transporter (SERT)‐positive fibres (−46%) and [ 3 H]‐paroxetine binding (−47%). In animals pre‐treated with MDMA there were widespread significant decreases in LCMRglu, but no change in LCBF indicating a persistent loss of cerebrovascular constrictor tone. In both pre‐treatment groups, acute MDMA produced significant increases in LCMRglu, while LCBF was significantly decreased. In 50% of MDMA‐pre‐treated rats, random areas of focal hyperaemia indicated a loss of autoregulatory capacity in response to MDMA‐induced hypertension. These results suggest that cerebrovascular regulatory dysfunction resulting from acute exposure to MDMA is not diminished by previous exposure, despite a significant depletion in 5‐HT terminals. However, there may be a sub‐population, or individual circumstances, in which this dysfunction develops into a condition that might predispose to stroke.