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Published on: September 23, 2015
Effect of 5-HT depletion by MDMA on hyperthermia and Arc mRNA induction in rat brain
Thomas J R Beveridge1, Annis O Mechan, Marie Sprakes
1School of Pharmacy, De Montfort University, Leicester, LE1 9BH, UK.
Rationale:
3,4-Methylenedioxymethamphetamine (MDMA) administration to rats produces an acute hyperthermic response and induces localised neuronal activation, which can be visualised via expression of immediate-early genes. The pharmacological and anatomical basis of these effects are unclear. At high doses, MDMA also causes selective neurotoxicity at serotonergic nerve terminals.
Objective:
We investigated the effect of 5-hydroxytryptamine (5-HT) depletion on the acute hyperthermic response to MDMA and the pattern of neuronal excitation indicated by Arc (activity-regulated cytoskeleton associated gene) in naive rats and following administration of MDMA at a neurotoxic dose.
Methods:
Expression of Arc mRNA was investigated by in situ hybridisation histochemistry using 35S-labelled oligonucleotide probe.
Results:
MDMA induced a significant hyperthermia together with increased Arc mRNA expression in cortical regions, caudate-putamen and CA1 hippocampus but not hypothalamus. At 21 days after a neurotoxic dose of MDMA, brain 5-HT and 5-HIAA levels were significantly reduced by 21-32%. In these animals, both the hyperthermic response and the pattern and extent of Arc mRNA expression induced by a subsequent dose of MDMA were unaltered. However, basal Arc expression was significantly increased in cortical regions and CA1 hippocampus.
Conclusion:
We conclude that the acute hyperthermic response induced by MDMA is not attenuated by moderate depletion of 5-HT, further questioning mediation via a serotonergic mechanism. Arc mRNA induction by MDMA exhibits highly localised expression, which is not altered following 5-HT depletion. However, following a neurotoxic dose of MDMA, basal expression of Arc is increased, particularly in cortex and CA1, suggesting that mechanisms underlying synaptic plasticity might also be modified.
Insights
3,4-Methylenedioxymethamphetamine (MDMA) causes hyperthermia and neuronal activation. Moderate depletion of serotonin did not alter these effects, suggesting non-serotonergic mechanisms are involved in MDMA
Area of Science:
- Neuroscience
- Pharmacology
- Molecular Biology
Background:
- 3,4-Methylenedioxymethamphetamine (MDMA) induces hyperthermia and neuronal activation in rats, visualized by immediate-early gene expression.
- The precise pharmacological and anatomical underpinnings of these MDMA effects remain unclear.
- High doses of MDMA can cause selective neurotoxicity to serotonergic nerve terminals.
Purpose of the Study:
- To investigate the impact of serotonin depletion on MDMA-induced hyperthermia.
- To examine how 5-hydroxytryptamine (5-HT) depletion affects neuronal excitation patterns, specifically activity-regulated cytoskeleton associated gene (Arc) expression, following MDMA administration.
- To compare these effects in naive rats versus those previously exposed to a neurotoxic dose of MDMA.
Main Methods:
- In situ hybridisation histochemistry was employed to detect Arc mRNA expression.
- A 35S-labelled oligonucleotide probe was utilized for accurate mRNA visualization.
- Serotonin (5-HT) and 5-hydroxyindoleacetic acid (5-HIAA) levels were measured in brain tissue.
Main Results:
- MDMA induced hyperthermia and increased Arc mRNA in cortical regions, caudate-putamen, and CA1 hippocampus, but not the hypothalamus.
- Twenty-one days after a neurotoxic MDMA dose, 5-HT and 5-HIAA levels were reduced by 21-32%.
- In serotonin-depleted rats, the hyperthermic response and Arc mRNA induction by MDMA were unchanged, though basal Arc expression increased in cortical regions and CA1 hippocampus.
Conclusions:
- The acute hyperthermic response to MDMA is not attenuated by moderate 5-HT depletion, questioning a serotonergic mechanism.
- MDMA-induced Arc mRNA expression is localized and unaffected by 5-HT depletion.
- Neurotoxic MDMA doses increase basal Arc expression, suggesting potential modifications to synaptic plasticity mechanisms.
