Discussion and Future Directions

Recent advances in the molecular biology of GABA receptors have provided tremendous opportunities for understanding actions of anesthetics and alcohol on these receptors. The availability of cDNAs encoding the receptor subunits, combined with expression systems and methods for the rapid intro-duction of mutations, has allowed rapid advances toward the 'Holy Grail' of anesthesia research: defining molecular sites of anesthetic action in the brain. There are tantalizing suggestions for an anesthetic binding site within GABA receptor subunits, but the low affinity of anesthetic bind-ing makes it difficult to prove rigorously that the anesthetic is indeed bindbind-ing at that site. Despite the obstacles it is likely that the site( s) of anesthetic and alcohol action on GABAA receptors will be defined to the satisfaction of many within a few years. These advances in molecular analysis will allow researchers to address the bigger question of which aspects of anesthetic and alcohol action are due to enhancement of GABAergic function. This will be accomplished by constructing mice with mutations in GABAA receptor subunits.

Targeted gene manipulations in mice will provide hypothesis-driven tests of the in vivo roles of certain ligand-gated ion channels in mediating the diverse behavioral actions of general anesthetics. Researchers over the last 5 years have created 'global knock-out mice' for various subunits of the ligand-gated ion channels. With the emergence of ligand-ligand-gated ion channel knock-out mice (and the commercial availability of some of these knock-knock-outs), it should prove useful to test anesthetic sensitivity in these mice. Although these knock-out mice may provide initial clues as to the nature of anesthetic targets, some mice will be difficult to analyze for anesthetic sensitivity if they exhibit abnormal behavior, lethality, or gross alterations in neural development. These problems with knock-out mice may be circumvented by 'conditional' gene knock-outs where the gene of interest is disrupted only in limited brain regions and/or specified developmental time periods (HOMANICS et a1. 1998). Another elegant example of gene targeting is the 'knock-in mouse.' One possibility is the introduction of the gene encoding a mutated receptor subunit that is insen-sitive to anesthetic modulation, in place of the normal endogenous gene

162 M.D. KRASOWSKI et al.

(LAKHLANI et al. 1997). Knock-in mouse experiments potentially provide an elegant bridge between in vitro experiments and whole animal behavior.

Ideally, the mutated receptor subunit would differ from the normal subunit only in terms of general anesthetic modulation (i.e., agonist response, voltage-dependence, kinetics, etc. of the receptor would be relatively normal) (RUDOLPH et al. 1999; McKERNAN et al. 2000). Recently described mutations within TM2 and TM3 of GABAA (see Figs. 2,4) and glycine receptors, which confer insensitivity to volatile ether anesthetics (MIHIC et al. 1997; KRASOWSKI et al. 1998b), n-alkanols (MIHIC et al. 1997; WICK et al. 1998; YE et al. 1998), propofol (KRASOWSKI et al.1998b), trichloroethanol (KRASOWSKI et al. 1998a), pentobarbitone (BIRNIR et al. 1997), and etomidate (BELELLI et al. 1997;

MCGURK et al. 1998) essentially fit this qualification. A complication to gene targeting experiments is the presence of multiple subunit isoforms for the GABAA receptor subunits; if some or all of these isoforms play a role in general anesthesia, targeting of multiple genes may be required to obtain a clear alteration in anesthetic sensitivity.

There is now ample evidence that clinical concentrations of most volatile or intravenous general anesthetics, including the n-alcohols, enhance the func-tion of GABAA receptors and we are on the verge of a molecular under-standing of the sites of action of these drugs on GABAA receptors. However, there is still little information, or at least agreement, about the consequence of actions of these agents on GABAA receptors. This is particularly true for ethanol, where pharmacological interest is focused on the actions of sub-anes-thetic doses, yet concentrations corresponding to these doses have small and variable effects on GABAA receptor function. This problem reflects our basic ignorance of how the brain works, in that we have no idea how small changes in channel function will influence behavior. We can be optimistic that con-struction of mice with mutant GABA receptors that differ in these subtle effects of anesthetics and alcohols will indeed address the fundamental ques-tion of how specific receptors influence specific behaviors. Indeed, recent work with the benzodiazepines suggests this era has already dawned.

Acknowledgments. We thank Dr. Caroline Rick for many helpful suggestions on this manuscript. Funding has been generously provided by NIH grants GM45129, GM56850, and GM00623 to N.L.H., by AA 03699 to R.A.H., by GM 47818 to R.A.H., N.L.H., and E. I. Eger II, and by NIMH training grant MH11504 to M.D.K.

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