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 breast cancer, has been shown previously to affect both estrogen-dependent 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 rat brain. Baseline data showed that, following a 2-h incubation, HTH and POA slices had comparable ATP levels to hippocampal slices, a system used extensively by researchers examining the metabolic responsiveness of the hippocampal region (HPC) of the brain. HTH-POA slice ATP levels 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 healthy and demonstrated robust protein synthesis as measured autoradiographically by incorporation of [H-3]leucine. We explored the effects of tamoxifen (TAM), fluphenazine (FLU) and estradiol (E-2) on ATP levels in HTH and POA slices. The effects of TAM were complex: a 4-h incubation 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 concentration 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 both TAM and FLU alter ATP levels in HTH slices via calmodulin- or calcium-mediated processes. (C) 1998 Elsevier Science B.V. All rights reserved.