ROLE OF GABA IN THE ACTIONS OF ETHANOL IN RATS SELECTIVELY BRED FOR ETHANOL SENSITIVITY

Rats from the Ni/Nih heterogeneous stock have been selectively bred fo r high (HAS) or low (LAS) initial sensitivity to injected ethanol as m easured by duration of the loss of the righting reflex. The selection for ethanol sensitivity in these lines apparently has reached a maximu m. These lines are useful to elucidate the central nervous system mech anisms of the genetic differences between the lines and also provide c lues to the mechanisms of ethanol's action. We have found that: 1) eth anol, etomidate, and ketamine but not propofol produce different sleep times and brain levels of the drug on awakening between these two lin es; 2) only ethanol, etomidate, and ketamine produced significant diff erences between the HAS and LAS rats in GABA-mediated stimulation of c hloride uptake into brain microsacs; 3) GABA, propofol, and etomidate decreased the K-d for flunitrazepam binding to whole-brain membranes b ut equally in both lines. Neither ethanol nor ketamine had an effect; 4) only GABA, ethanol, and etomidate increased the K-d for TBPS bindin g and only GABA decreased B-max of TBPS binding. As with the previous selection for ethanol sensitivity in mice (short and long sleep) these lines of rats have very marked line differences in GABA-mediated even ts, and these are correlated with the sedative effects of ethanol. Fro m these and previous studies we know that the major differences betwee n selected lines of mice and rats are that the mouse lines are not dif ferentially sensitive to halothane or pentobarbital white the rat line s are. However, the mouse lines are differentially sensitive to propof ol and the rat lines are not. These data should be useful in dissectin g the actions of ethanol at the GABA(A) receptor. (C) 1998 Elsevier Sc ience Inc.