PMID- 20962361
OWN - NLM
STAT- MEDLINE
DCOM- 20110324
LR  - 20131121
IS  - 1419-8711 (Print)
IS  - 1419-8711 (Linking)
VI  - 12
IP  - 3
DP  - 2010 Sep
TI  - Long-term neuronal damage and recovery after a single dose of MDMA: expression 
      and distribution of serotonin transporter in the rat brain.
PG  - 413-23
AB  - "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.
FAU - Kirilly, Eszter
AU  - Kirilly E
AD  - Semmelweis University, Department of Pharmacodynamics, Budapest, Hungary.
LA  - eng
PT  - Journal Article
PL  - Hungary
TA  - Neuropsychopharmacol Hung
JT  - Neuropsychopharmacologia Hungarica : a Magyar Pszichofarmakologiai Egyesulet 
      lapja = official journal of the Hungarian Association of Psychopharmacology
JID - 100961631
RN  - 0 (RNA, Messenger)
RN  - 0 (Serotonin Plasma Membrane Transport Proteins)
RN  - 333DO1RDJY (Serotonin)
RN  - KE1SEN21RM (N-Methyl-3,4-methylenedioxyamphetamine)
SB  - IM
MH  - Aggression/*drug effects
MH  - Animals
MH  - Basal Metabolism
MH  - Brain/*drug effects/*metabolism/physiopathology
MH  - Gene Expression Regulation
MH  - Genetic Predisposition to Disease
MH  - Humans
MH  - Immunohistochemistry
MH  - In Situ Hybridization
MH  - Male
MH  - N-Methyl-3,4-methylenedioxyamphetamine/administration & 
      dosage/metabolism/pharmacology/*toxicity
MH  - Neurons/*drug effects/metabolism
MH  - RNA, Messenger/metabolism
MH  - Raphe Nuclei/drug effects/metabolism
MH  - Rats
MH  - Risk Factors
MH  - Serotonin/genetics/*metabolism
MH  - Serotonin Plasma Membrane Transport Proteins/drug effects/*metabolism
MH  - Sleep/*drug effects
MH  - Substance-Related Disorders/complications/metabolism
MH  - Time Factors
MH  - Wakefulness/drug effects
EDAT- 2010/10/22 06:00
MHDA- 2011/03/25 06:00
CRDT- 2010/10/22 06:00
PHST- 2010/10/22 06:00 [entrez]
PHST- 2010/10/22 06:00 [pubmed]
PHST- 2011/03/25 06:00 [medline]
PST - ppublish
SO  - Neuropsychopharmacol Hung. 2010 Sep;12(3):413-23.