Short- and long-term effects of p-ethynylphenylalanine on brain serotonin levels

[en] Changes in tissue and extracellular serotonin (5-HT) in raphe dorsalis, raphe medialis and in their main projections areas (hippocampus, striatum and frontal cortex) were investigated at short and long-term times after single injection (5 mg/kg ip) of a novel tryptophan hydroxylase inhibitor, p-ethynylphenylalanine (p-EPA). The 5-HT tissue concentration decreased significantly in raphe nuclei, 30 min post-injection and for 4 days, whereas it decreased from 24 hours post-injection in the 5-HT projections. Normal 5-HT levels reappeared after 12 days post-injection in all areas. Moreover, in the projection areas, the extracellular 5-HT levels decreased rapidly, 90, 40 and 30 min after p-EPA injection, in hippocampus, striatum and frontal cortex, respectively. Decreased accumulation of 5-hydroxytryptophan (5-HTP) under NSD-101 perfusion in the serotoninergic projections after p-EPA injection, confirmed the direct inhibitory effect of the drug on the tryptophan hydroxylase activity. These results demonstrated that p-EPA is a useful pharmacological tool which powerfully, acutely and irreversibly reduces the 5-HT levels.

Research center :

GIGA CRC (Cyclotron Research Center) In vivo Imaging-Aging & Memory - ULiège

Disciplines :

Life sciences: Multidisciplinary, general & others

Author, co-author :

Zimmer, Luc; CERMEP

Luxen, André ; Université de Liège - ULiège > Département de chimie (sciences) > Chimie organique de synthèse - Centre de recherches du cyclotron

Giacomelli, Fabrice ; Université de Liège - ULiège > Centre de recherches du cyclotron

Pujol, Jean-François

Language :

English

Title :

Short- and long-term effects of p-ethynylphenylalanine on brain serotonin levels

Publication date :

April 2002

Journal title :

Neurochemical Research

ISSN :

0364-3190

eISSN :

1573-6903

Publisher :

Kluwer Academic/Plenum Publ, New York, United States - New York

Volume :

Issue :

Pages :

269-275

Peer reviewed :

Peer Reviewed verified by ORBi

Additional URL :

http://www.springerlink.com/content/lk1jl16qfax66nbe/

Available on ORBi :

since 26 October 2010

Statistics

Number of views

49 (10 by ULiège)

Number of downloads

1 (1 by ULiège)

More statistics

Scopus citations^®

Scopus citations^®
without self-citations

OpenCitations

Bibliography

Azmitia E.C., Segal M. (1978) An autoradiographic analysis of the differential ascending projections of the dorsal and median raphe nuclei in the rat. J. Comp. Neurol. 179:641-668.
Molliver M.E. (1987) Serotoninergic neuronal systems: What their anatomic organization tells us about function. J. Clin. Psychopharmacol. 7.
Weissmann D., Chamba G., Debure L., Rousset C., Richard F., Maitre M., Pujol J.F. (1990) Variation of tryptophan-5-hydroxylase concentration in the rat raphe dorsalis nucleus after p-chlorophenylalanine administration. II. Anatomical distribution of the tryptophan-5-hydroxylase protein and regional variation of its turnover rate. Brain Res. 17:46-55.
Raison S., Weissmann D., Rousset C., Pujol J.F., Descarries L. (1995) Changes in steady-state levels of tryptophan hydroxylase protein in adult rat brain after neonatal 6-hydroxydopamine lesion. Neuroscience 67:463-475.
Koe K.B., Weissman A. (1966) p-chlorophenylalanine: A specific depletor of brain serotonin. J. Pharmacol. Exp. Ther. 154:499-516.
Stokes A.H., Xu Y., Daunais J.A., Tamir H., Gershon M.D., Butkerait P., Kayser B., Altman J., Beck W., Vrana K.E. (2000) p-ethynylphenylalanine: A potent inhibitor of tryptophan hydroxylase. J. Neurochem. 74:2067-2073.
Cumming P., Brown E., Damsma G., Fibiger H. (1992) Formation and clearance of interstitial metabolites of dopamine and serotonin in the rat striatum: An in vivo microdialysis study. J. Neurochem. 59:1905-1914.
Finlay J.M., Zigmond M.J. (1995) A critical analysis of neurochemical methods for monitoring transmitter dynamics in the brain. Psychopharmacology: The fourth generation of progress , Bloom, F. E., and Kupfer, D. J. (eds.), Raven Press, New York; 29-40.
Hashiguti H., Nakahara D., Maruyama W., Naoi M., Ikeda T. (1993) Simultaneous determination of in vivo hydroxylation of tyrosine and tryptophan in rat striatum by microdialysis-HPLC: Relationship between dopamine and serotonin biosynthesis. J. Neural. Transm. 93:213-223.
Nakahara D., Nakamura M. (1999) Differential effect of immobilization stress on in vivo synthesis rate of monoamines in medial prefrontal cortex and nucleus accumbens of conscious rats. Synapse 32:238-242.
Nakahara D., Nakamura M., Furukawa H., Furuno N. (2000) Intracranial self-stimulation increases differentially in vivo hydroxylation of tyrosine but similarly in vivo hydroxylation of tryptophan in rat medial prefrontal cortex, nucleus accumbens and striatum. Brain Res. 864:124-129.
Kayser B., Altman J., Beck W. (1997) Alkyne bridged α-amino acids by palladium mediated coupling of alkynes with N-t-Boc-4-iodophenylalanine methyl ester. Tetrahedron 53:2475-2484.
Paxinos G., Watson C. The Rat Brain in Stereotaxic Coordinates, Academic Press, New-York; 1986.
Adell A., Carceller A., Artigas F. (1991) Regional distribution of extracellular 5-hydroxytryptamine and 5-hydroxyindoleacetic acid in the brain of freely moving rats. J. Neurochem. 56:709-712.
Dewar K.M., Reader T.A., Grondin L., Descarries L. (1991) [3] paroxetine binding and serotonin content of rat and rabbit cortical areas, hippocampus, neostriatum, ventral mesencephalic tegmentum, and midbrain raphe nuclei region. Synapse 9:14-26.
Reader T.A. (1982) Catecholamines and serotonin in rat frontal cortex after PCPA and 6-OHDA: Absolute amounts and ratios. Brain Res. Bull. 8:527-534.
Knapp S., Mandell A.J. (1972) Parachlorophenylalanine - Its three phase sequence of interactions with the two forms of brain tryptophan hydroxylase. Life Sci. 11:761-771.
Lookingland K.J., Shannon N.J., Chapin D.S., Moore K.E. (1986) Exogenous tryptophan increases synthesis, storage, and intraneuronal metabolism of 5-hydroxytryptamine in the rat hypothalamus. J. Neurochem. 47:205-212.
Wright I.K., Garrat J.C., Marsden C.A. (1990) Effect of a selective 5-HT2 agonist, DOI, on 5-HT neuronal firing in the dorsal raphe nucleus and 5-HT release and metabolism in the frontal cortex. Br. J. Pharmacol. 99:211-222.
Steinbusch H.W.M., Nieuwenhuys R., Verhofstad A.A.J., Van der Kooy D. (1981) The nucleus raphe dorsalis of the rat and its projection upon the caudatoputamen. A combined cytoarchitectonic, immunohistochemical and retrograde transport study. J. Physiol. 77:157-174.
Meek J.L., Neff N.H. (1972) Tryptophan 5-hydroxylase: Approximation of half-life and rate of axonal transport. J. Neurochem. 19:1519-1525.
Miller K.J., Anderholm D.C., Ames M.M. (1986) Metabolic activation of the serotonergic neurotoxin parachloroamphetamine to chemically reactive intermediates by hepatic and brain microsomal preparations. Biochem. Pharmacol. 15:1737-1742.
Richard F., Sanne J.L., Bourde O., Weissmann D., Ehret M., Cash C., Maître M., Pujol J.F. (1990) Variation of tryptophan-5-hydroxylase concentration in the rat raphe dorsalis nucleus after p-chlorophenylalanine administration. I. A model to study the turnover of the enzymatic protein. Brain Res. 536:41-45.