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Restoration of 3,4-methylenedioxymethamphetamine-induced 5-HT depletion by the administration of L-5-hydroxytryptophan.
Neuroscience. 2007 Aug 10; 148(1):212-20.N

Abstract

BACKGROUND

3,4-Methylenedioxymethamphetamine (MDMA) causes persistent decreases in brain 5-HT content and 5-HT transporter (SERT) binding, with no detectable changes in SERT protein. Such data suggest that MDMA impairs 5-HT transmission but leaves 5-HT nerve terminals intact. To further test this hypothesis, we carried out two types of experiments in rats exposed to high-dose MDMA. First, we examined the effects of MDMA on SERT binding and function using different in vitro assay conditions. Next, we treated rats with the 5-HT precursor, l-5-hydroxytryptophan (5-HTP), in an attempt to restore MDMA-induced depletions of 5-HT.

METHODS

Rats received three i.p. injections of saline or MDMA (7.5 mg/kg), one injection every 2 h. Rats in one group were decapitated, and brain tissue was assayed for SERT binding and [(3)H]5-HT uptake under conditions of normal (100 or 126 mM) and low (20 mM) NaCl concentration. Rats from another group received saline or 5-hydroxytryptophan/benserazide (5-HTP-B), each drug at 50 mg/kg i.p., and were killed 2 h later.

RESULTS

MDMA reduced SERT binding to 10% of control when assayed in 100 mM NaCl, but this reduction was only 55% of control in 20 mM NaCl. MDMA decreased immunoreactive 5-HT in caudate and hippocampus to about 35% of control. Administration of 5-HTP-B to MDMA-pretreated rats significantly increased the 5-HT signal toward normal levels in caudate (85% of control) and hippocampus (66% of control).

CONCLUSION

1) Following high-dose MDMA treatment sufficient to reduce SERT binding by 90%, a significant number of functionally intact 5-HT nerve terminals survive. 2) The degree of MDMA-induced decreases in SERT binding depends on the in vitro assay conditions. 3) 5-HTP-B restores brain 5-HT depleted by MDMA, suggesting that this approach might be clinically useful in abstinent MDMA users.

Authors+Show Affiliations

Clinical Psychopharmacology Section, Intramural Research Program, National Institute on Drug Abuse, National Institutes of Health, P.O. Box 5180, 5500 Nathan Shock Drive, Baltimore, MD 21224, USA.No affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Journal Article
Research Support, N.I.H., Intramural

Language

eng

PubMed ID

17629409

Citation

Wang, X, et al. "Restoration of 3,4-methylenedioxymethamphetamine-induced 5-HT Depletion By the Administration of L-5-hydroxytryptophan." Neuroscience, vol. 148, no. 1, 2007, pp. 212-20.
Wang X, Baumann MH, Dersch CM, et al. Restoration of 3,4-methylenedioxymethamphetamine-induced 5-HT depletion by the administration of L-5-hydroxytryptophan. Neuroscience. 2007;148(1):212-20.
Wang, X., Baumann, M. H., Dersch, C. M., & Rothman, R. B. (2007). Restoration of 3,4-methylenedioxymethamphetamine-induced 5-HT depletion by the administration of L-5-hydroxytryptophan. Neuroscience, 148(1), 212-20.
Wang X, et al. Restoration of 3,4-methylenedioxymethamphetamine-induced 5-HT Depletion By the Administration of L-5-hydroxytryptophan. Neuroscience. 2007 Aug 10;148(1):212-20. PubMed PMID: 17629409.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Restoration of 3,4-methylenedioxymethamphetamine-induced 5-HT depletion by the administration of L-5-hydroxytryptophan. AU - Wang,X, AU - Baumann,M H, AU - Dersch,C M, AU - Rothman,R B, Y1 - 2007/07/12/ PY - 2007/04/02/received PY - 2007/05/21/revised PY - 2007/05/26/accepted PY - 2007/7/17/pubmed PY - 2007/12/15/medline PY - 2007/7/17/entrez SP - 212 EP - 20 JF - Neuroscience JO - Neuroscience VL - 148 IS - 1 N2 - BACKGROUND: 3,4-Methylenedioxymethamphetamine (MDMA) causes persistent decreases in brain 5-HT content and 5-HT transporter (SERT) binding, with no detectable changes in SERT protein. Such data suggest that MDMA impairs 5-HT transmission but leaves 5-HT nerve terminals intact. To further test this hypothesis, we carried out two types of experiments in rats exposed to high-dose MDMA. First, we examined the effects of MDMA on SERT binding and function using different in vitro assay conditions. Next, we treated rats with the 5-HT precursor, l-5-hydroxytryptophan (5-HTP), in an attempt to restore MDMA-induced depletions of 5-HT. METHODS: Rats received three i.p. injections of saline or MDMA (7.5 mg/kg), one injection every 2 h. Rats in one group were decapitated, and brain tissue was assayed for SERT binding and [(3)H]5-HT uptake under conditions of normal (100 or 126 mM) and low (20 mM) NaCl concentration. Rats from another group received saline or 5-hydroxytryptophan/benserazide (5-HTP-B), each drug at 50 mg/kg i.p., and were killed 2 h later. RESULTS: MDMA reduced SERT binding to 10% of control when assayed in 100 mM NaCl, but this reduction was only 55% of control in 20 mM NaCl. MDMA decreased immunoreactive 5-HT in caudate and hippocampus to about 35% of control. Administration of 5-HTP-B to MDMA-pretreated rats significantly increased the 5-HT signal toward normal levels in caudate (85% of control) and hippocampus (66% of control). CONCLUSION: 1) Following high-dose MDMA treatment sufficient to reduce SERT binding by 90%, a significant number of functionally intact 5-HT nerve terminals survive. 2) The degree of MDMA-induced decreases in SERT binding depends on the in vitro assay conditions. 3) 5-HTP-B restores brain 5-HT depleted by MDMA, suggesting that this approach might be clinically useful in abstinent MDMA users. SN - 0306-4522 UR - https://www.unboundmedicine.com/medline/citation/17629409/Restoration_of_34_methylenedioxymethamphetamine_induced_5_HT_depletion_by_the_administration_of_L_5_hydroxytryptophan_ L2 - https://linkinghub.elsevier.com/retrieve/pii/S0306-4522(07)00673-2 DB - PRIME DP - Unbound Medicine ER -