Abstract
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.
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REFERENCES
Azmitia, E. C. and 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. 7:3S-23S.
Weissmann, D., Chamba, G., Debure, L., Rousset, C., Richard, F., Maitre, M., and 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., and 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. and 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., and Vrana, K. E. 2000. p-Ethynylphenylalanine: a potent inhibitor of tryptophan hydroxylase. J. Neurochem. 74:2067–2073.
Cumming, P., Brown, E., Damsma, G., and 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. and Zigmond, M. J. 1995. A critical analysis of neurochemical methods for monitoring transmitter dynamics in the brain. Pages 29–40, in Bloom, F. E., and Kupfer, D. J. (eds.), Psychopharmacology: The fourth generation of progress, Raven Press, New York.
Hashiguti, H., Nakahara, D., Maruyama, W., Naoi, M., and 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. and 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., and 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., and Beck, W. 1997. Alkyne bridged a-amino acids by palladium mediated coupling of alkynes with N-t-Boc-4–iodophenylalanine methyl ester. Tetrahedron 53:2475–2484.
Paxinos, G. and Watson, C. (eds.) 1986. The Rat Brain in Stereotaxic Coordinates. Academic Press, New-York.
Adell, A., Carceller, A., and 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., and Descarries, L. 1991. [3H] 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. and 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., and 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., and 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., and 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. and 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., and 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., and 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.
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Zimmer, L., Luxen, A., Giacomelli, F. et al. Short- and Long-Term Effects of p-Ethynylphenylalanine on Brain Serotonin Levels. Neurochem Res 27, 269–275 (2002). https://doi.org/10.1023/A:1014998926763
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DOI: https://doi.org/10.1023/A:1014998926763