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*Compound via MeSH
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Hazardous Substances DB
*NICOTINE
*NICOTINE TARTRATE
*TRITIUM

Vol. 287, Issue 2, 648-657, November 1998

Pharmacological Characterization of Nicotinic Receptor-stimulated GABA Release From Mouse Brain Synaptosomes1

Ying Lu, Sharon Grady, Michael J. Marks, Marina Picciotto2, Jean-Pierre Changeux3 and Allan C. Collins

Institute for Behavioral Genetics, University of Colorado, Boulder, Colorado

Several recent electrophysiological studies have demonstrated that nicotinic agonists stimulate the release of gamma -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-beta -erythroidine. alpha -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 (alpha 4beta 2). Unequivocal evidence that the receptor that modulates nicotine-stimulated [3H]-GABA release contains a beta 2 subunit was obtained in a study using wild-type, heterozygous and homozygous beta 2 null mutant mice. [3H]-GABA release and [3H]-nicotine binding decreased along with the number of copies of the null mutant gene.

0022-3565/98/2872-0648$03.00/0
THE JOURNAL OF PHARMACOLOGY AND EXPERIMENTAL THERAPEUTICS
Copyright © 1998 by The American Society for Pharmacology and Experimental Therapeutics


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