RT Journal Article
SR Electronic
T1 Pharmacological Characterization of Nicotinic Receptor-stimulated GABA Release From Mouse Brain Synaptosomes
JF Journal of Pharmacology and Experimental Therapeutics
JO J Pharmacol Exp Ther
FD American Society for Pharmacology and Experimental Therapeutics
SP 648
OP 657
VO 287
IS 2
A1 Ying Lu
A1 Sharon Grady
A1 Michael J. Marks
A1 Marina Picciotto
A1 Jean-Pierre Changeux
A1 Allan C. Collins
YR 1998
UL http://jpet.aspetjournals.org/content/287/2/648.abstract
AB 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 (Emax). The EC50 and Emax values were significantly correlated (r = 0.95, P < .001 for EC50; r = 0.93, P < .01 for Emax) to values obtained for these same agonists when 86Rb+ efflux was determined. A significant correlation (r = 0.84, P < .01) was found when the EC50 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. The American Society for Pharmacology and Experimental Therapeutics