Abstract
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]γ-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 (onsetT1/2 = 3.46 min) and was totally reversible (recovery T1/2 = 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 IC50 value of 26 nM. This value is two orders of magnitude lower than the EC50for 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 (86Rb+) efflux that we have measured previously suggests that the receptor that mediates GABA release and86Rb+ efflux is the same, most likely the α4β2 subtype.
Footnotes
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Send reprint requests to: Allan C. Collins, Institute for Behavioral Genetics, University of Colorado, Campus Box 447, Boulder, CO 80309-0447. E-mail:al.collins{at}colorado.edu
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↵1 This work was supported by Grants DA-03194 and AA-10156. A.C.C. is supported, in part, by a Research Scientist Award from National Institute on Drug Abuse (DA-00197).
- Abbreviations:
- GABA
- α-aminobutyric acid
- DFP
- diisopropylfluorophosphate
- Ach
- acetylcholine
- Received May 11, 1999.
- Accepted August 17, 1999.
- The American Society for Pharmacology and Experimental Therapeutics
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