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

Several neurochemical and electrophysiological studies have shown that neur onal nicotinic receptors are desensitized by pretreatment with lower agonis t concentrations than are required to activate the receptors, but the exten t of desensitization and agonist concentration required to produce desensit ization vary depending upon receptor subtype. Recently, we reported that ni cotinic agonists will stimulate the release of [H-3]gamma-aminobutyric acid (GABA) from synaptosomes prepared from mouse brain. The studies described herein evaluated desensitization of [H-3]GABA release produced by pretreatm ent with 12 nicotinic agonists. Pretreatment produced near total desensitiz ation that developed slowly (onset T-1/2 = 3.46 min) and was totally revers ible (recovery T-1/2 = 4.95 min). Nine of the 12 compounds tested induced t otal or near total desensitization at concentrations that were less than th ose required to produce a reliably measured increase in [H-3]GABA release. Nicotine produced total block with an IC50 value of 26 nM. This value is tw o orders of magnitude lower than the EC50 for nicotine-induced [H-3]GABA re lease (1630 nM). The three compounds that showed an overlap of the desensit ization and activation concentration-effect curves (cytisine, anabasine, no rnicotine) are all partial agonists. Comparison of the desensitization prop erties of the [H-3]GABA release with an ion (Rb-86(+)) efflux that we have measured previously suggests that the receptor that mediates GABA release a nd Rb-86(+) efflux is the same, most likely the alpha 4 beta 2 subtype.