Long-term neuronal damage and recovery after a single dose of MDMA: expression and distribution of serotonin transporter in the rat brain.
"Ecstasy", 3,4-methylenedioxymethamphetamine (MDMA), an amphetamine analogue is one of the most widely used recreational drugs. In spite of the fact that neurotoxic effects of MDMA has been found in several species from rodents to non-human primates, and results increasingly point to damage also in human MDMA users, data about the sensitivity of different brain areas and the recovery after neuronal damage are scarce. Serotonin transporter (5-HTT) mRNA in the raphe nuclei also has not been examined. Humans with genetic predisposition for the slow metabolism of MDMA, the so-called "poor metabolizers" of debrisoquin are at higher risk. Five- 9% of the Caucasian population is considered to carry this phenotype. These studies were carried out in Dark Agouti rats, a special strain that show decreased microsomal CYP2D1 isoenzyme activity, and thus may serve as a model of vulnerable human users. These works were designed to characterize MDMA-induced damage and recovery of the serotonergic system including sleep and morphological changes within 180 days. In our experiments we investigated the 5-HTT mRNA expression in the brainstem and medullary raphe nuclei, 5-HTT immunoreactive (IR) fibre densities in several brain areas, and 16 functional measures of sleep in response to a single dose of +/- MDMA (15mg\kg). Furthermore, behavioural experiments were performed 21 days after MDMA treatment. We found similar changes in 5-HTT mRNA expression in the examined raphe nuclei, namely transient increases 7 days after MDMA treatment followed by transient decreases at 21 days. Significant (20-40%), widespread reductions in 5-HTT-IR fibre density were detected in most brain areas at 7 and 21 days after MDMA administration. All cortical, but only some brainstem areas were damaged. Parallel to the neuronal damage we observed significant reductions in rapid eye movement (REM) sleep latency, increased fragmentation of sleep and increases in delta power spectra in non-REM sleep. At 180 days almost all functional changes in sleep were normalized together with 5-HTT mRNA expression in the examined raphe nuclei and the recovery of 5-HTT-IR fibre density in most brain areas. Our results also suggest that the acute MDMA administration abolished aggressive behaviour but MDMA pretreatment and the consequent depletion of serotonergic terminals did not affect aggression. Our findings concerning the changes detected in 5-HTT mRNA expression and fibre density indicate lasting impairment of the serotonergic system and suggest that a single use of MDMA may be associated with long-lasting cognitive, learning, memory and mood deficits and sleep disturbances particularly when a constellation of genetic vulnerability and certain environmental factors are present. Our data provide further evidence for the connection between altered serotonergic functions and sleep disturbance.
Semmelweis University, Department of Pharmacodynamics, Budapest, Hungary.
Eszter
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Kirilly
D000374:Aggression / Q000187:drug effects*; D000818:Animals; D001481:Basal Metabolism; D001921:Brain / Q000187:drug effects* / Q000378:metabolism* / Q000503:physiopathology; D005786:Gene Expression Regulation; D020022:Genetic Predisposition to Disease; D006801:Humans; D007150:Immunohistochemistry; D017403:In Situ Hybridization; D008297:Male; D018817:N-Methyl-3,4-methylenedioxyamphetamine / Q000008:administration & dosage / Q000378:metabolism / Q000494:pharmacology / Q000633:toxicity*; D009474:Neurons / Q000187:drug effects* / Q000378:metabolism; D012333:RNA, Messenger / Q000378:metabolism; D011903:Raphe Nuclei / Q000187:drug effects / Q000378:metabolism; D051381:Rats; D012307:Risk Factors; D012701:Serotonin / Q000235:genetics / Q000378:metabolism*; D050486:Serotonin Plasma Membrane Transport Proteins / Q000187:drug effects / Q000378:metabolism*; D012890:Sleep / Q000187:drug effects*; D019966:Substance-Related Disorders / Q000150:complications / Q000378:metabolism; D013997:Time Factors; D014851:Wakefulness / Q000187:drug effects
D012333:RNA, Messenger; D050486:Serotonin Plasma Membrane Transport Proteins; D012701:Serotonin; D018817:N-Methyl-3,4-methylenedioxyamphetamine