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Adaptive Plasticity in the Hippocampus of Young Mice Intermittently Exposed to MDMA Could Be the Origin of Memory
S Abad1, J Camarasa1, D Pubill1
1Department of Pharmacology and Therapeutic Chemistry (Pharmacology Section), Faculty of Pharmacy, University of Barcelona, Avda. Joan XXIII s/n., Barcelona, 08028, Spain.
Abstract:
(±)3,4-Methylenedioxymethamphetamine (MDMA) is a relatively selective dopaminergic neurotoxin in mice. This study was designed to evaluate whether MDMA exposure affects their recognition memory and hippocampal expression of plasticity markers. Mice were administered with increasing doses of MDMA once per week for 8 weeks (three times in 1 day, every 3 h) and killed 2 weeks (2w) or 3 months (3m) later. The treatment did not modify hippocampal tryptophan hydroxylase 2, a serotonergic indicator, but induced an initial reduction in dopaminergic markers in substantia nigra, which remained stable for at least 3 months. In parallel, MDMA produced a decrease in dopamine (DA) levels in the striatum at 2w, which were restored 3 months later, suggesting dopaminergic terminal regeneration (sprouting phenomenon). Moreover, recognition memory was assessed using the object recognition test. Young (2w) and mature (3m) adult mice exhibited impaired memory after 24-h but not after just 1-h retention interval. Two weeks after the treatment, animals showed constant levels of CREB but an increase in its phosphorylated form and in c-Fos expression. Brain-derived neurotrophic factor (BDNF) and especially Arc overexpression was sustained and long-lasting. We cannot rule out the absence of MDMA injury in the hippocampus being due to the generation of BDNF. The levels of NMDAR2B, PSD-95, and synaptophysin were unaffected. In conclusion, the young mice exposed to MDMA showed increased expression of early key markers of plasticity, which sometimes remained for 3 months, and suggests hippocampal maladaptive plasticity that could explain memory deficits evidenced here.
Insights
MDMA exposure in mice impaired recognition memory and altered hippocampal plasticity markers. Dopaminergic changes and increased plasticity indicators suggest maladaptive neural responses.
Area of Science:
- Neuroscience
- Neuropharmacology
- Molecular Biology
Background:
- 3,4-Methylenedioxymethamphetamine (MDMA) is recognized for its neurotoxic potential, particularly affecting dopaminergic pathways.
- Understanding MDMA's long-term effects on cognitive function and neural plasticity is crucial for assessing its risks.
Purpose of the Study:
- To investigate the impact of chronic MDMA administration on recognition memory in mice.
- To examine the expression of hippocampal plasticity markers following MDMA exposure.
- To evaluate the persistence of these effects over time.
Main Methods:
- Mice received escalating doses of MDMA weekly for 8 weeks.
- Recognition memory was assessed using the object recognition test at 2 weeks and 3 months post-treatment.
- Hippocampal expression of plasticity markers (e.g., CREB, c-Fos, BDNF, Arc) and dopaminergic markers were analyzed.
Main Results:
- MDMA exposure led to impaired recognition memory with a 24-hour retention interval.
- Dopaminergic markers in the striatum initially decreased but showed signs of regeneration by 3 months.
- Increased expression of plasticity markers, including CREB phosphorylation, c-Fos, BDNF, and Arc, was observed, with some sustained long-term.
- No significant changes were found in NMDAR2B, PSD-95, or synaptophysin.
Conclusions:
- MDMA exposure induces maladaptive hippocampal plasticity in young mice, potentially explaining memory deficits.
- The observed sustained increase in plasticity markers suggests long-lasting neural adaptations.
- Brain-derived neurotrophic factor (BDNF) may play a role in mitigating direct hippocampal injury from MDMA.
