The estrogen receptor modulator tamoxifen enhances spontaneous glycinergic synaptic inhibition of hypoglossal motoneurons

Tamoxifen (Tam), a widely used anticancer agent, is now also used for healthy women with risk of breast cancer. Furthermore, it is the prototype of the selective estrogen receptor modulator family, with promise for neuroprotection. However, possible effects on neurotransmission have been little explored. Recently, Tam was shown to potentiate chloride responses to low concentrations of exogenous glycine in cultured spinal neurons from rat embryo. The present study investigates the possible modulation by Tam of the spontaneous synaptic glycinergic activity recorded from voltage-clamped hypoglossal motoneurons, using the whole-cell patch-clamp technique in brainstem slices from juvenile rat. Miniature currents were isolated with tetrodotoxin. Tam increased the mean amplitude of glycinergic miniature currents, by 68-79% at 2 mu M (in nine of 10 cells) and by 47% at 0.5 mu M (in four of nine cells). Furthermore, Tam markedly increased the frequency of glycinergic miniatures, by a factor reaching 15 in some neurons, even in the presence of the Ca2+ channel blocker Cd2+. Tam also increased the frequency of the total spontaneous glycinergic activity without tetrodotoxin. The increase in miniature amplitude is consistent with the increase in postsynaptic glycine receptor sensitivity previously reported. The increase in frequency indicates an additional presynaptic effect. Addition of exogenous glycine could also increase the frequency of glycinergic miniatures. Thus, one of the presynaptic effects of Tam might be potentiation of the basal activity of presynaptic glycine receptors facilitating glycine release. Possible risks related to modulation of glycinergic neurotransmission by Tam should be considered when recommending its use in healthy individuals.