Effects of tamoxifen on striatal dopamine and 5-hydroxytryptamine release in freely moving male rats: An in-vivo microdialysis investigation

Recent studies indicating interaction of oestrogens with central cholinergi c, dopaminergic and 5-HTergic systems have led to the assumption of a prote ctive role of oestrogens in certain neurodegenerative disorders. The non-st eroidal drug tamoxifen, a mixed oestrogen agonist-antagonist, has been show n to modulate central nervous system functions in the corpus striatum. In t his study we used a microdialysis technique to examine the effects of tamox ifen upon the striatal dopaminergic and 5-HTergic systems in intact freely moving male rats. The extracellular levels of dopamine, 3,4-dihydroxyphenylacetic acid, homov anillic acid and 5-hydroxyindoleacetic acid were measured after intraperito neal administration of either the control or tamoxifen, and were compared w ith their corresponding baseline levels. Significant 25-35% increases in th e baseline levels of dopamine and 3,4-dihydroxyphenylacetic acid were obser ved after the highest doses of tamoxifen (1.5 mg kg(-1) and 3.0 mg kg(-1) r espectively), whereas the lowest dose of tamoxifen (0.3 mg kg(-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-dopa mine remained unchanged in comparison with that of the pretreatment levels. Whereas no change in the striatal 5-hydroxyindoleacetic acid concentration s was seen with the lowest and highest dose regimen, the intermediate dose elicited a moderate increase (20%) in basal 5-hydroxyindoleacetic acid leve ls. The pharmacological relevance of the effects of tamoxifen on the dopaminerg ic and 5-HTergic systems, as a prelude to the development of non-steroidal oestrogenic compounds in reducing the risk of neurodegenerative disorders s uch as Alzheimer's disease, is discussed.