Over-expression of the fyn-kinase gene reduces hypnotic sensitivity to ethanol in mice

Our previous work indicated a role for fyn-kinase in mediating several ethanol- and GABA(A) agonist-mediated behaviors. In the present work we investigate behavioral sensitivity to ethanol and several GABA(A) compounds in mice that over-express fyn-kinase in forebrain to further characterize the role of this non-receptor tyrosine kinase in the mediation of ethanol sensitivity. Transgenic mice over-expressing fyn-kinase were tested for sensitivity to ethanol-induced loss of righting reflex and ethanol preference drinking using a two-bottle choice drinking paradigm. Loss of righting reflex induced by 4,5,6,7-tetrahydroisoxazolo[5,4-c]pyridin-3-ol (THIP; GABA(A) agonist) and etomidate (GABA(A) positive allosteric modulator) were also assessed. Fyn over-expressing mice exhibited shorter durations of ethanol-induced loss of righting reflex in the absence of differences in the rate of blood ethanol clearance, and exhibited reduced ethanol preference drinking. The genotypes did not differ in initial sensitivity to ethanol-induced loss of righting reflex suggesting development of greater acute tolerance to this ethanol action. Fyn over-expressing and wild-type mice also did not differ in sensitivity to loss of righting reflex induced by THIP and etomidate. The present results suggest regional specificity for fyn-kinase in the modulation of ethanol and GABAergic behavioral sensitivity. Fyn-kinase over-expression in forebrain structures modulates ethanol's hypnotic actions, as well as ethanol preference and consumption. Moreover, fyn over-expression in forebrain does not alter hypnotic sensitivity to THIP or etomidate, supporting data from fyn null mutant mice suggesting that cerebellar structures mediate the hypnotic actions of these GABAergic compounds.