Potentiation of glycine responses by dideoxyforskolin and tamoxifen in rat spinal neurons

Dideoxyforskolin, a forskolin analogue unable to stimulate adenylate cyclase, and tamoxifen, an antioestrogen widely used against breast cancer, are both known to block some Cl − channels. Their effects on Cl − responses to glycine or GABA have been tested here by using whole‐cell recording from cultured spinal neurons. Dideoxyforskolin (4 or 16 µ m ) and tamoxifen (0.2–5 µ m ) both potentiate responses to low glycine concentrations. They also induce blocking effects, predominant at high glycine concentrations. At 5 µ m , tamoxifen increased responses to 15 µ m glycine by a factor >4.5, reaching 20 in some neurons. Potentiation by extracellular dideoxyforskolin or tamoxifen persisted after intracellular application of the modulator and was not due to Zn 2+ contamination. Potentiation by tamoxifen also persisted in a Ca 2+ ‐free extracellular solution, after intracellular Ca 2+ buffering and protein kinase C blockade. Thus, the critical sites of action are not intracellular. The EC 50 for glycine was lowered 6.6‐fold by 5 µ m tamoxifen. The kinetics and voltage‐dependence of the effects of tamoxifen on glycine responses support the idea that this hydrophobic drug may act from a site located within the membrane. Tamoxifen (5 µ m ) also increased responses to 2 µ m GABA by a factor of 3.5, but barely affected peak responses to 20 µ m GABA. The demonstration that tamoxifen affects some of the main inhibitory receptors should be useful for better evaluating its neurological effects. Furthermore, the results identify a new class of molecules that potentiate glycine receptor function.