PMID- 18515011 OWN - NLM STAT- MEDLINE DCOM- 20081105 LR - 20211020 IS - 0306-4522 (Print) IS - 0306-4522 (Linking) VI - 155 IP - 1 DP - 2008 Jul 31 TI - 3,4-Methylenedioxymethamphetamine induces differential regulation of tryptophan hydroxylase 2 protein and mRNA levels in the rat dorsal raphe nucleus. PG - 270-6 LID - 10.1016/j.neuroscience.2008.03.086 [doi] AB - Previous investigations with 3,4-methylenedioxymethamphetamine (MDMA) have suggested that administration of this drug results in a degeneration of 5-HT nerve terminals and subsequent alterations in 5-HT neurotransmission. However, only limited investigations have examined the effects of MDMA on the dorsal raphe nucleus. The present study was designed to assess the effect of MDMA on the rate-limiting enzyme in 5-HT biosynthesis, tryptophan hydroxylase (TPH), by measuring TPH2 protein and mRNA levels in rat dorsal raphe (DR) nucleus. Rats were administered MDMA (20 mg/kg, s.c.) or saline twice daily for 4 days and killed 14 days later. Tissue sections of the DR were processed for quantitative immunoautoradiography and in situ hybridization histochemistry for measurements of the levels of TPH2-immunoreactivity (IR) and TPH2 mRNA. To assess 5-HT axon terminal integrity after MDMA treatment, the density of 5-HT transporter (SERT) binding sites was measured by quantitative autoradiography using [125I]RTI-55 ((-)-2beta-carbomethoxy-3 beta-(4-iodophenyl) tropane) ((125)I-RTI-55) as a ligand. TPH2-IR levels were significantly decreased by 45% in the mid DR and by 40% in the caudal DR in the MDMA-treated rats compared with saline-injected rats. In contrast, TPH2 mRNA levels were significantly increased by 24% in the mid DR and by 12% in the caudal DR. MDMA treatment significantly decreased (125)I-RTI-55 labeled SERT binding sites in the striatum, nucleus accumbens and cingulate cortex demonstrating a loss of 5-HT terminals. The increase in TPH2 mRNA levels in both the mid DR and caudal DR of MDMA-treated rats may reflect a compensatory mechanism in the injured 5-HT neurons to increase TPH2 protein synthesis. Taken together, our results suggest that a serious defect occurs in the biosynthesis of TPH2 in the DR following MDMA administration. FAU - Bonkale, W L AU - Bonkale WL AD - Department of Psychiatry and Behavioral Science, Neuropsychiatry Research Program (151N), TX A & M University System HSC and Central Texas Veterans Health Care System, Temple, TX 76504, USA. wbonkale@medicine.tamhsc.edu FAU - Austin, M C AU - Austin MC LA - eng GR - R01 MH057011-03/MH/NIMH NIH HHS/United States GR - P20 RR017701-067501/RR/NCRR NIH HHS/United States GR - P20 RR017701/RR/NCRR NIH HHS/United States GR - MH 57011/MH/NIMH NIH HHS/United States GR - P20 RR017701-067504/RR/NCRR NIH HHS/United States GR - RR 17701/RR/NCRR NIH HHS/United States PT - Journal Article PT - Research Support, N.I.H., Extramural DEP - 20080416 PL - United States TA - Neuroscience JT - Neuroscience JID - 7605074 RN - 0 (RNA, Messenger) RN - 0 (Serotonin Agents) RN - 0 (Serotonin Plasma Membrane Transport Proteins) RN - EC 1.14.16.4 (Tryptophan Hydroxylase) RN - EC 1.14.16.4 (tph2 protein, rat) RN - KE1SEN21RM (N-Methyl-3,4-methylenedioxyamphetamine) SB - IM MH - Animals MH - Autoradiography/methods MH - Gene Expression Regulation/drug effects MH - Male MH - N-Methyl-3,4-methylenedioxyamphetamine/*pharmacology MH - Protein Binding/drug effects MH - RNA, Messenger/*metabolism MH - Raphe Nuclei/*drug effects/metabolism MH - Rats MH - Rats, Sprague-Dawley MH - Serotonin Agents/*pharmacology MH - Serotonin Plasma Membrane Transport Proteins/metabolism MH - Tryptophan Hydroxylase/*genetics/*metabolism PMC - PMC2505057 MID - NIHMS60770 EDAT- 2008/06/03 09:00 MHDA- 2008/11/06 09:00 PMCR- 2008/08/11 CRDT- 2008/06/03 09:00 PHST- 2008/01/22 00:00 [received] PHST- 2008/03/15 00:00 [revised] PHST- 2008/03/28 00:00 [accepted] PHST- 2008/06/03 09:00 [pubmed] PHST- 2008/11/06 09:00 [medline] PHST- 2008/06/03 09:00 [entrez] PHST- 2008/08/11 00:00 [pmc-release] AID - S0306-4522(08)00529-0 [pii] AID - 10.1016/j.neuroscience.2008.03.086 [doi] PST - ppublish SO - Neuroscience. 2008 Jul 31;155(1):270-6. doi: 10.1016/j.neuroscience.2008.03.086. Epub 2008 Apr 16.