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Research ArticleArticle

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

Ying Lu, Sharon Grady, Michael J. Marks, Marina Picciotto, Jean-Pierre Changeux and Allan C. Collins
Journal of Pharmacology and Experimental Therapeutics November 1998, 287 (2) 648-657;
Ying Lu
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Sharon Grady
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Michael J. Marks
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Marina Picciotto
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Jean-Pierre Changeux
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Allan C. Collins
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Abstract

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.

Footnotes

  • Send reprint requests to: Dr. Allan C. Collins, Institute for Behavioral Genetics, Campus Box 447, University of Colorado, Boulder, CO 80309-0447.

  • ↵1 This work was supported by Grants DA-03194 and DA-00197 from the United States National Institute on Drug Abuse and by the Collège de France, the Centre National de la Recherche Scientifique, the Association Française contre la Myopathie, the Council for Tobacco Research, a Biotech contract from the Commission of the European Communities.

  • ↵2 Current address: Department of Psychiatry, Yale University School of Medicine, New Haven, CT 05508.

  • ↵3 Current address: URA CNRS 1284, Neurobiologie Moleculaire, Institut Pasteur, Paris, France.

  • Abbreviations:
    Ach
    acetylcholine
    nAChR
    nicotinic cholinergic receptors
    GABA
    γ-aminobutyric acid
    DHβE
    dihydro-β-erythroidine
    TTX
    tetrodotoxin
    DMPP
    dimethylphenyl piperazinium
    DFP
    diisopropyl flourophosphate
    α-BTX
    α-bungarotoxin
    HEPES
    N-[2-hydroxyethyl]-piperazine-N′-[2-ethanesulfonate] hemisodium salt
    CNQX
    6-cyano-7-nitroquinoxaline-2.3-dione
    R(+)-SCH23390
    R(+)-7-chloro-8-hydroxy-3-methyl-1-phenyl-2.3.4.5-tetrahydro-1H-3-benzazepine hydrochloride, MDL-72222, 3-tropanyl-3.5-dichlorobenzoate
    AP-5
    DL-2-amino-5-phosphonopentanoic acid
    • Received April 8, 1998.
    • Accepted June 18, 1998.
  • The American Society for Pharmacology and Experimental Therapeutics
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Journal of Pharmacology and Experimental Therapeutics
Vol. 287, Issue 2
1 Nov 1998
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Research ArticleArticle

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

Ying Lu, Sharon Grady, Michael J. Marks, Marina Picciotto, Jean-Pierre Changeux and Allan C. Collins
Journal of Pharmacology and Experimental Therapeutics November 1, 1998, 287 (2) 648-657;

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Research ArticleArticle

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

Ying Lu, Sharon Grady, Michael J. Marks, Marina Picciotto, Jean-Pierre Changeux and Allan C. Collins
Journal of Pharmacology and Experimental Therapeutics November 1, 1998, 287 (2) 648-657;
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