Desensitization of nicotinic agonist-induced [3H]gamma-aminobutyric acid release from mouse brain synaptosomes is produced by subactivating concentrations of agonists.

Several neurochemical and electrophysiological studies have shown that neuronal nicotinic receptors are desensitized by pretreatment with lower agonist concentrations than are required to activate the receptors, but the extent of desensitization and agonist concentration required to produce desensitization vary depending upon receptor subtype. Recently, we reported that nicotinic agonists will stimulate the release of [3H]gamma-aminobutyric acid (GABA) from synaptosomes prepared from mouse brain. The studies described herein evaluated desensitization of [3H]GABA release produced by pretreatment with 12 nicotinic agonists. Pretreatment produced near total desensitization that developed slowly (onset T(1/2) = 3.46 min) and was totally reversible (recovery T(1/2) = 4.95 min). Nine of the 12 compounds tested induced total or near total desensitization at concentrations that were less than those required to produce a reliably measured increase in [3H]GABA release. Nicotine produced total block with an IC(50) value of 26 nM. This value is two orders of magnitude lower than the EC(50) for nicotine-induced [3H]GABA release (1630 nM). The three compounds that showed an overlap of the desensitization and activation concentration-effect curves (cytisine, anabasine, nornicotine) are all partial agonists. Comparison of the desensitization properties of the [3H]GABA release with an ion ((86)Rb+) efflux that we have measured previously suggests that the receptor that mediates GABA release and (86)Rb(+) efflux is the same, most likely the alpha4beta2 subtype.