EFFECTS OF TAMOXIFEN, FLUPHENAZINE AND ESTRADIOL ON ATP LEVELS IN PREOPTIC AREA AND HYPOTHALAMIC SLICES FROM OVARIECTOMIZED RATS

Tamoxifen, the major adjuvant drug treatment for estrogen-dependent br east cancer, has been shown previously to affect both estrogen-depende nt and calcium/calmodulin-dependent pathways. In the current study, we developed an in vitro slice system to study the effects of tamoxifen on ATP levels in hypothalamic (HTH) and preoptic areas (POA) of the ra t brain. Baseline data showed that, following a 2-h incubation, HTH an d POA slices had comparable ATP levels to hippocampal slices, a system used extensively by researchers examining the metabolic responsivenes s of the hippocampal region (HPC) of the brain. HTH-POA slice ATP leve ls remained steady for 2, 4 and 6 h, but fell to 11% of initial levels by 12 h. Neurons from HTH-POA slices incubated for 4 h appeared healt hy and demonstrated robust protein synthesis as measured autoradiograp hically by incorporation of [H-3]leucine. We explored the effects of t amoxifen (TAM), fluphenazine (FLU) and estradiol (E-2) on ATP levels i n HTH and POA slices. The effects of TAM were complex: a 4-h incubatio n with 10(-6) M TAM led to decreased ATP levels in HTH (but not POA), and a 4-h incubation with 10(-8) M led to increased ATP levels in POA (but not HTH); a 15-min exposure to 10-6 M TAM decreased ATP levels in POA (but not HTH) slices, while the exposure of slices to the lower c oncentration of TAM was without effect in either area. As with higher concentrations of TAM, 4-h incubation with 10(-6) M FLU decreased ATP levels in HTH (but not POA), while incubation with E-2 did not affect slice ATP levels. These data are consistent with the hypothesis that b oth TAM and FLU alter ATP levels in HTH slices via calmodulin- or calc ium-mediated processes. (C) 1998 Elsevier Science B.V. All rights rese rved.