We investigated the estrogen agonist/antagonist properties of the selective estrogen receptor modulators (SERMs), tamoxifen (TMX) and 4-hydroxy-tamoxifen (OHT), using an in vitro neuron model system to determine the impact of the neuroprotective and neurotrophic properties of these SERMs. Low concentrations of TMX or OHT were without effect on a marker of neuronal viability, basal release of lactate dehydrogenase (LDH), whereas high concentrations of both SERMs (2500 ng/ml) induced a significant increase in LDH, indicating the potential toxicity of both SERMs at high concentrations. Subsequent experiments revealed that subtoxic concentrations of both TMX and OHT induced significant neuroprotection against beta-amyloid(25-35)-induced toxicity; 15-20% and 10-15% (P < 0.05), respectively and also against glutamate-induced toxicity; 25-30% and 20-40% (P < 0.05 and P < 0.01), respectively. Additional in vitro experiments included analysis of neuron survival to determine whether the SERM, OHT, acted competitively or synergistically with the endogenous estrogen, 17 beta-estradiol (E2). These revealed that neuron survival following exposure to the neurotoxins beta-amyloid and excitotoxic glutamate was significantly increased in cultures treated with OHT (50 ng/ml) (10%, P < 0.01) and that the magnitude of survival was equivalent to E2 (10 ng/ml). The combined presence of OHT and E2 significantly protected against both beta-amyloid(25-35) and excitotoxic glutamate-induced neuron death (10%, P < 0.01) but was not significantly different from either OHT or E2 alone. To assess neurotrophic effects of these same SERMs, cultured neurons from brain regions involved in memory function and Alzheimer's disease were evaluated by morphological analysis of individual neurons. Results of these analyses demonstrated that TMX treatment did not significantly increase the process outgrowth or morphological complexity of cortical, hippocampal, or basal forebrain neurons. Similar analyses showed that OHT also failed to significantly increase the neuronal outgrowth of either cortical or hippocampal neurons. Results of these studies predict that TMX and OHT could exert a neuroprotective function but would not promote estrogen-dependent memory function.