Neuropharmacology: Effects of Tamoxifen on Striatal Dopamine and 5-Hydroxytryptamine Release in Freely Moving Male Rats: An In-vivo Microdialysis Investigation

Authors


Food and Drug Administration Division of Bioequivalence, Room 123, Metropark North II, 7500 Standish Place, Rockville, MD 20855, USA.

Abstract

Recent studies indicating interaction of oestrogens with central cholinergic, dopaminergic and 5-HTergic systems have led to the assumption of a protective role of oestrogens in certain neurodegenerative disorders. The non-steroidal drug tamoxifen, a mixed oestrogen agonist—antagonist, has been shown to modulate central nervous system functions in the corpus striatum. In this study we used a microdialysis technique to examine the effects of tamoxifen upon the striatal dopaminergic and 5-HTergic systems in intact freely moving male rats.

The extracellular levels of dopamine, 3,4-dihydroxyphenylacetic acid, homovanillic acid and 5-hydroxyindoleacetic acid were measured after intraperitoneal administration of either the control or tamoxifen, and were compared with their corresponding baseline levels. Significant 25–35% increases in the baseline levels of dopamine and 3,4-dihydroxyphenylacetic acid were observed after the highest doses of tamoxifen (1.5mgkg−1 and 3.Omgkg−1, respectively), whereas the lowest dose of tamoxifen (0.3mgkg−1) elevated dopamine and 3,4-dihydroxyphenylacetic acid levels by a detectable 15% of the basal. In addition, the ratio of 3,4-dihydroxyphenylacetic acid-to-dopamine remained unchanged in comparison with that of the pretreatment levels. Whereas no change in the striatal 5-hydroxyindoleacetic acid concentrations was seen with the lowest and highest dose regimen, the intermediate dose elicited a moderate increase (20%) in basal 5-hydroxyindoleacetic acid levels.

The pharmacological relevance of the effects of tamoxifen on the dopaminergic and 5-HTergic systems, as a prelude to the development of non-steroidal oestrogenic compounds in reducing the risk of neurodegenerative disorders such as Alzheimer's disease, is discussed.

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