Abstract
Benzodiazepines are neuromodulatory drugs that potentiate GABA-mediated conductance increases. We report the findings of an investigation into the effect of a full benzodiazepine-positive modulator (agonist), chlordiazepoxide (CDPX), on desensitization of the GABA response in chick spinal cord neurons maintained in primary monolayer cell culture. GABA application initially increases cell conductance, which then desensitizes. CDPX increases the apparent rate constant and extent of desensitization for the GABA response. The observed values for rate constant and extent of desensitization in the presence of CDPX are significantly greater than the values predicted for an equivalent peak response to GABA alone. Flunitrazepam, another full positive modulator, also stimulates the rate constant for GABA-induced desensitization. Furthermore, a weak partial benzodiazepine-positive modulator, Ro 15- 1788 (an imidazodiazepine) (1) exhibits little or no potentiation of GABA-induced desensitization, and (2) antagonizes the ability of CDPX to stimulate GABA desensitization. The results demonstrate a novel form of neuromodulator action: the stimulation of receptor desensitization that cannot be explained by channel blockade. Thus, benzodiazepine modulators have the capacity to increase GABA receptor desensitization while increasing the peak response to GABA.