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BEHAVIORAL PHARMACOLOGY

Deletion of the fyn-Kinase Gene Alters Sensitivity to GABAergic Drugs: Dependence on 2/3 GABA_A Receptor Subunits

Waggoner Center for Alcohol and Addiction Research, University of Texas at Austin, Austin, Texas

Tyrosine phosphorylation can modulate GABA_A receptor function, and deletion of the fyn-kinase gene alters GABAergic function in olfactory bulb neurons, as reported by Kitazawa, Yagi, Miyakawa, Niki, and Kawai (J Neurophysiol 1998;79:137-142). Our goal was to determine whether fyn gene deletion altered behavioral and functional actions of compounds that act on GABA_A receptors. Such evidence might suggest a role for fyn-kinase in modulating GABA_A receptor function, possibly via direct interactions between the kinase and receptor. Using the loss of righting reflex test, we found that null mutants were less sensitive to the hypnotic effects of THIP (4,5,6,7-tetrahydroisoxazolo[5,4-c]pyridin-3-ol), a GABA_A receptor agonist. Subunit specificity was suggested by the observation that null mutants were also less sensitive to the hypnotic effects of etomidate, a GABAergic compound that is selective for receptors possessing 2 and/or 3 receptor subunits. The genotypes did not differ in sensitivity to zolpidem, an 1-selective GABAergic drug. GABA_A receptor functional assays (³⁶Cl^- influx) supported our behavioral results; the actions of the GABA_A agonists, THIP and muscimol, were reduced in the cerebellar membranes of fyn-null mutant mice. Importantly, similar results were seen with etomidate. Binding of [³H]flunitrazepam supported the idea that this is due to a decrease in functional GABA_A receptor density. These data suggest that fyn-kinase may alter the function of GABA_A receptors, perhaps via actions on 2 and/or 3 receptor subunits.

Address correspondence to: Stephen Boehm II, University of Texas at Austin, Waggoner Center for Alcohol and Addiction Research, 1 University Station A4800, Austin TX, 78712-0159. E-mail: slboehm{at}mail.utexas.edu