The antiestrogen, tamoxifen (TMX), has been used extensively in the treatment, and now for the potential prevention of breast cancer in women. Therefore, it is clear that increasing numbers of women will be receiving TMX in the future. In addition to exerting effects upon putative reproductive organs responsive to estrogen, there is evidence that TMX can also influence the central nervous system. The purpose of this proposal will be to examine some of the effects of TMX upon the nigrostriatal dopaminergic (NSDA) system. The selection of this site is based upon data which show that the NSDA system represents an important target for estrogen and contains the second highest concentration of estradiol within the brain suggesting that antiestrogenic agents may similarly modulate activity at this site. In the first part of this proposal (Questions 1 and 2), two different conditions of TMX treatment upon motor behaviors and striatal dopamine concentration and release in vitro will be examined - duration of TMX treatment and age of the animal to whom TMX is administered. The second part (Questions 3 and 4) represents an attempt to understand further some of the mechanisms by which TMX may alter striatal dopaminergic function and consists of infusing this antiestrogen directly into superfused striatal tissue fragments in which the medium is rich or deficient in calcium. In this way, it will be possible to evaluate the overall effects of TMX upon NSDA function and initiate work whose goals will be to understand how this antiestrogen may directly alter dopamine release within the striatum.
