A study on the mechanism by which MDMA protects against dopaminergic dysfunction after minimal traumatic brain injury (mTBI) in mice.

Abstract

Driving under methylenedioxymethamphetamine (MDMA) influence increases the risk of being involved in a car accident, which in turn can lead to traumatic brain injury. The behavioral deficits after traumatic brain injury (TBI) are closely connected to dopamine pathway dysregulation. We have previously demonstrated in mice that low MDMA doses prior to mTBI can lead to better performances in cognitive tests. The purpose of this study was to assess in mice the changes in the dopamine system that occurs after both MDMA and minimal traumatic brain injury (mTBI). Experimental mTBI was induced using a concussive head trauma device. One hour before injury, animals were subjected to MDMA. Administration of MDMA before injury normalized the alterations in tyrosine hydroxylase (TH) levels that were observed in mTBI mice. This normalization was also able to lower the elevated dopamine receptor type 2 (D2) levels observed after mTBI. Brain-derived neurotrophic factor (BDNF) levels did not change following injury alone, but in mice subjected to MDMA and mTBI, significant elevations were observed. In the behavioral tests, haloperidol reversed the neuroprotection seen when MDMA was administered prior to injury. Altered catecholamine synthesis and high D2 receptor levels contribute to cognitive dysfunction, and strategies to normalize TH signaling and D2 levels may provide relief for the deficits observed after injury. Pretreatment with MDMA kept TH and D2 receptor at normal levels, allowing regular dopamine system activity. While the beneficial effect we observe was due to a dangerous recreational drug, understanding the alterations in dopamine and the mechanism of dysfunction at a cellular level can lead to legal therapies and potential candidates for clinical use.

• Authors: S Edut, V Rubovitch, M Rehavi, S Schreiber, C G Pick
• Journal: Journal of molecular neuroscience : MN (J Mol Neurosci) Vol. 54 Issue 4 Pg. 684-97 (Dec 2014) ISSN: 1559-1166 [Electronic] United States
• PMID: 25124230 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Brain-Derived Neurotrophic Factor
• Catecholamines
• Receptors, Dopamine D2
• Tyrosine 3-Monooxygenase
• Haloperidol
• N-Methyl-3,4-methylenedioxyamphetamine

Topics

• Animals
• Brain (drug effects, metabolism)
• Brain Concussion (metabolism, prevention & control)
• Brain-Derived Neurotrophic Factor (genetics, metabolism)
• Catecholamines (metabolism)
• Dopaminergic Neurons (drug effects, metabolism, physiology)
• Haloperidol (pharmacology)
• Mice
• Mice, Inbred ICR
• N-Methyl-3,4-methylenedioxyamphetamine (pharmacology, therapeutic use)
• Receptors, Dopamine D2 (genetics, metabolism)
• Tyrosine 3-Monooxygenase (genetics, metabolism)