Pharmacological characterization of nicotinic receptor-stimulated GABA release from mouse brain synaptosomes

Ying Lu, Sharon Grady, Michael J. Marks, Marina Picciotto, Jean Pierre Changeux, Allan C. Collins

Research output: Contribution to journalArticlepeer-review


Several recent electrophysiological studies have demonstrated that nicotinic agonists stimulate the release of γ-aminobutyric acid (GABA) from rodent brain tissue. Our studies used a neurochemical approach to characterize nicotinic receptor-stimulated [3H]-GABA release from mouse brain synaptosomes. Nicotine increased [3H]-GABA release from synaptosomes preloaded with [3H]-GABA in a concentration-dependent manner. This release appeared rapidly, was Ca++ dependent, and was partially (about 50%) blocked by 100 nM tetrodotoxin and totally blocked by mecamylamine and dihydro-β- erythroidine. α-Bungarotoxin had no effect. Twelve nicotinic agonists were compared for their effects on [3H]-GABA release. The agonists differed in potency (EC50) and efficacy (E(max)). The ECsc and E(max) values were significantly correlated (r = 0.95, P < .001 for EC50; r = 0.93, P < .01 for E(max)) to values obtained for these same agonists when 86Rb+ efflux was determined. A significant correlation (r = 0.84, P < .01) was found when the ECsc values for agonist-stimulated [3H]-GABA release and IC50 values for agonist inhibition of [3H]-L-nicotine binding were compared. Differences in [3H]-GABA release were detected in 12 brain regions and maximal release was significantly correlated with [3H]-nicotine binding. The pharmacological and regional comparisons suggest that the nAChR that stimulates [3H]-GABA release is the one that binds [3H]-nicotine with high affinity (α4β2). Unequivocal evidence that the receptor that modulates nicotine-stimulated [3H]-GABA release contains a β2 subunit was obtained in a study using wild- type, heterozygous and homozygous β2 null mutant mice. [3H]-GABA release and [3H]-nicotine binding decreased along with the number of copies of the null mutant gene.

Original languageEnglish (US)
Pages (from-to)648-657
Number of pages10
JournalJournal of Pharmacology and Experimental Therapeutics
Issue number2
StatePublished - 1998

ASJC Scopus subject areas

  • Molecular Medicine
  • Pharmacology


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