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In vitro neuronal and vascular responses to 5-HT in rats chronically exposed to MDMA
D M Cannon1, A K Keenan, P J Guiry
1Department of Pharmacology, Conway Institute of Biomolecular and Biomedical Research, University College Dublin, Belfield, Dublin 4, Ireland.
Abstract:
1. This study examined the effects of chronic exposure of rats to 3,4-methylenedioxymethamphetamine (MDMA) on [(3)H]5-hydroxytryptamine ([(3)H]5-HT) re-uptake into purified rat brain synaptosomes, 5-HT-induced isometric contraction of aortic rings and [(3)H]5-HT re-uptake into rat aorta. 2. Rats were administered MDMA (20 mg kg(-1) i.p.) twice daily over 4 days. One, 7, 14 or 21 days post treatment, whole brain synaptosomes and descending thoracic aortic rings were prepared for investigation. 3. Chronic MDMA treatment significantly reduced the maximum rate (V(max)) of specific high-affinity [(3)H]5-HT re-uptake 1 day after treatment and for up to 21 days post-final administration of MDMA. Direct application of MDMA (100 microM) abolished synaptosomal re-uptake of [(3)H]5-HT in vitro. 4. Chronic MDMA administration significantly reduced the maximum contraction (E(max)) to 5-HT at 1 and 7 days after treatment, but not at 14 or 21 days. 5. Chronic MDMA administration had no effect on sodium-dependent [(3)H]5-HT re-uptake into aorta 1 day after treatment, nor did 100 microM MDMA have any direct effect on [(3)H]5-HT uptake into aortic rings in vitro. 6. These results show, for the first time, an altered responsiveness of vascular tissue to MDMA after chronic administration. In addition, they demonstrate a difference in the sensitivity of central and peripheral 5-HT uptake systems to chronic MDMA exposure, and suggest that the action of MDMA in the cardiovascular system does not arise from a direct effect of MDMA on peripheral 5-HT transport.
Insights
Chronic exposure to 3,4-methylenedioxymethamphetamine (MDMA) significantly impairs serotonin (5-HT) re-uptake in rat brains for up to 21 days. Vascular tissue shows altered responsiveness to MDMA, but not direct impairment of peripheral 5-HT transport.
Area of Science:
- Neuroscience
- Pharmacology
- Cardiovascular Science
Background:
- 3,4-methylenedioxymethamphetamine (MDMA) is a recreational drug with known neurotoxic effects.
- Serotonin (5-HT) plays a crucial role in both central nervous system function and peripheral vascular regulation.
- The long-term cardiovascular and neurochemical effects of chronic MDMA exposure require further elucidation.
Purpose of the Study:
- To investigate the impact of chronic MDMA administration on serotonin re-uptake in rat brain synaptosomes.
- To assess the effects of chronic MDMA on 5-HT-induced vascular contractions and serotonin re-uptake in rat aorta.
- To determine the duration of these effects and differentiate central versus peripheral mechanisms.
Main Methods:
- Rats received MDMA (20 mg/kg) twice daily for 4 days.
- Serotonin re-uptake was measured in brain synaptosomes and aortic rings at 1, 7, 14, and 21 days post-treatment.
- Isometric contractions of aortic rings in response to 5-HT were also assessed.
Main Results:
- Chronic MDMA significantly reduced serotonin re-uptake in brain synaptosomes for up to 21 days.
- MDMA exposure reduced 5-HT-induced aortic ring contraction at 1 and 7 days post-treatment, but not later.
- No direct effect of MDMA on peripheral serotonin re-uptake in the aorta was observed.
Conclusions:
- Chronic MDMA administration leads to persistent deficits in central serotonin re-uptake.
- Vascular responsiveness to serotonin is altered following chronic MDMA, indicating peripheral effects.
- The cardiovascular actions of MDMA are unlikely to stem from direct interference with peripheral serotonin transport.