Differential long-term effects of MDMA on the serotoninergic system and hippocampal cell proliferation in 5-HTT knock-out vs. wild-type mice.
Although numerous studies investigated the mechanisms underlying 3,4-methylenedioxymethamphetamine (MDMA)-induced neurotoxicity, little is known about its long-term functional consequences on 5-HT neurotransmission in mice. This led us to evaluate the delayed effects of MDMA exposure on the 5-HT system, using in-vitro and in-vivo approaches in both 5-HTT wild-type and knock-out mice. Acute MDMA in-vitro application on slices of the dorsal raphe nucleus (DRN) induced concentration-dependent 5-HT release and 5-HT cell firing inhibition. Four weeks after MDMA administration (20 mg/kg b.i.d for 4 d), a 2-fold increase in the potency of the 5-HT1A receptor agonist ipsapirone to inhibit the discharge of DRN 5-HT neurons and a larger hypothermic response to 8-OH-DPAT were observed in MDMA- compared to saline-treated mice. This adaptive 5-HT1A autoreceptor supersensitivity was associated with decreases in 5-HT levels but no changes of [3H]citalopram binding in brain. Long-term MDMA treatment also induced a 30% decrease in BrdU labelling of proliferating hippocampal cells and an increased immobility duration in the forced swim test suggesting a depressive-like behaviour induced by MDMA treatment. All these effects were abolished in 5-HTT-/- knock-out mice. These data indicated that, in mice, MDMA administration induced a delayed adaptive supersensitivity of 5-HT1A autoreceptors in the DRN, a deficit in hippocampal cell proliferation and a depressive-like behaviour. These 5-HTT-dependent effects, opposite to those of antidepressants, might contribute to MDMA-induced mood disorders.
Renoir
Thibault
T
INSERM, U677, Paris, F-75013, France.
Païzanis
Eleni
E
El Yacoubi
Malika
M
Saurini
Françoise
F
Hanoun
Naïma
N
Melfort
Maxette
M
Lesch
Klaus Peter
KP
Hamon
Michel
M
Lanfumey
Laurence
L
D017371:8-Hydroxy-2-(di-n-propylamino)tetralin / Q000494:pharmacology; D000818:Animals; D049109:Cell Proliferation / Q000187:drug effects; D015283:Citalopram / Q000378:metabolism; D004594:Electrophysiology; D005260:Female; D006213:Hallucinogens / Q000494:pharmacology*; D019417:Hindlimb Suspension / Q000523:psychology; D006624:Hippocampus / Q000166:cytology* / Q000187:drug effects / Q000378:metabolism; D007274:Injections, Intraperitoneal; D008297:Male; D008566:Membranes / Q000187:drug effects / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D018817:N-Methyl-3,4-methylenedioxyamphetamine / Q000494:pharmacology*; D018408:Patch-Clamp Techniques; D011903:Raphe Nuclei / Q000166:cytology / Q000187:drug effects; D044402:Receptor, Serotonin, 5-HT2A / Q000187:drug effects / Q000235:genetics / Q000502:physiology; D012701:Serotonin / Q000378:metabolism / Q000502:physiology*; D018490:Serotonin Agents / Q000494:pharmacology*; D050486:Serotonin Plasma Membrane Transport Proteins / Q000235:genetics* / Q000502:physiology*; D017366:Serotonin Receptor Agonists / Q000494:pharmacology; D017367:Selective Serotonin Reuptake Inhibitors / Q000378:metabolism; D013550:Swimming / Q000523:psychology
D017371:8-Hydroxy-2-(di-n-propylamino)tetralin; D015283:Citalopram; D006213:Hallucinogens; D018817:N-Methyl-3,4-methylenedioxyamphetamine; D044402:Receptor, Serotonin, 5-HT2A; D012701:Serotonin; D018490:Serotonin Agents; D050486:Serotonin Plasma Membrane Transport Proteins; D017366:Serotonin Receptor Agonists; D017367:Selective Serotonin Reuptake Inhibitors; C493231:Slc6a4 protein, mouse