Acute methylenedioxymethamphetamine administration: effects on local cerebral blood flow and glucose utilisation in the Dark Agouti rat.

RATIONALE: Clinical reports indicate that acute exposure to 3,4-methylenedioxymethamphetamine (MDMA; "Ecstasy") may induce pathological cerebrovascular responses in human users of the drug, however, the mechanism by which MDMA might effect these pathological changes is not clear. OBJECTIVES: To examine the effects of acute MDMA administration on the relationship between local cerebral blood flow (LCBF) and local cerebral glucose utilisation (LCMRglu); to determine the effect, if any, acute exposure to MDMA has on the cerebral circulation, independently of alterations in cerebral metabolic demand. METHODS: Dark Agouti rats were injected with 15 mg.kg(-1) i.p. MDMA or saline equivalent. LCBF and LCMRglu were measured in 50 brain areas using the fully quantitative [14C]iodoantipyrine and [14C]2-deoxyglucose autoradiographic techniques, respectively. RESULTS: MDMA produced significant increases in LCMRglu in 23 brain areas, most markedly in the motor system (globus pallidus; +82%; medial striatum; +71%). In contrast, significant decreases in LCBF were observed in 28 brain areas, most markedly in primary sensory nuclei (superior colliculus; -32%) and limbic areas (anterior thalamus; -34%). Global analysis revealed a close correlation (r=0.87) between LCMRglu and LCBF with a ratio of 1.53 in controls. Despite the divergence of LCMRglu (increases) and LCBF (decreases) in MDMA-treated groups, there was a similar close correlation (r=0.84), but the ratio was decreased to 1.22. CONCLUSIONS: This study provides clear evidence that acute exposure to MDMA results in cerebrovascular dysfunction. The uncoupling of LCBF from underlying metabolic demand, possibly due to the vasoconstrictor action of 5-HT, could provide the basis for oligaemia-induced pathological changes in the brain.

Functional consequences of perinatal exposure to 3,4-methylenedioxymethamphetamine in rat brain.

1. In this study we have examined methylenedioxymethamphetamine (MDMA)-induced toxicity in perinatal rat brain, related this to normal development of serotonin transporter sites (SERT), and determined whether early exposure to MDMA subsequently alters cerebral function in adults. 2. Perinatal development of SERT was visualized and quantified using [(3)H]-paroxetine binding autoradiography in embryonic and neonatal rat brain from embryonic day 15 (E15) to postnatal day p30 (p30). Cerebral glucose utilization (lCMR(glu)) was measured by 2-deoxyglucose autoradiography in adult rats. 3. [(3)H]-Paroxetine binding was observed in forebrain from E18. From birth (p0), binding was organized into neocortical columns (75% higher at p10 than in adult) which declined toward adult levels between p20 and p25. 4. MDMA treatment (20 mg x kg(-1) s.c. twice daily for four days) commencing at developmental stages from E15 (treatment given to dams) to p20, had no effect upon [(3)H]-paroxetine binding measured at p40. Treatments started on p25 or later resulted in significant decreases in [(3)H]-paroxetine binding (>or=46%). This was coincident with the development of adult patterns of binding in forebrain. 5. Despite the lack of MDMA-induced neurotoxicity, rats treated in utero (E15) showed increased lCMR(glu) in locus coeruleus (+37%), and in areas receiving ascending noradrenergic innervation, such as anterior thalamus (+44%) and septal nucleus (+24%). 6 These studies confirm that the susceptibility of serotonergic terminals to the neurotoxic properties of MDMA is absent in the immediate perinatal period, but also suggests that in utero MDMA exposure produces significant long-term effects on cerebral function by a mechanism as yet unknown.