I am very pleased to learn that my 1995 Pharmacological Reviews article, "Structure and pharmacology of gamma-aminobutyric acid_A receptor subtypes," was such a success and that so many scientists have cited it! Actually, I have been involved in GABA_A receptor research since 1979. Coming back to the Department of Biochemical Psychiatry, University Clinic for Psychiatry, Vienna, Austria, from my second post-doc in Paul Greengard’s lab at the Department of Pharmacology, Yale University, I was looking for a research field of some clinical importance. When I learned that Hanns Möhler has demonstrated that [³H]flunitrazepam could be used as a photolabel for benzodiazepine receptors (Möhler et al., PNAS 77: 1666-1670, 1980), I immediately tried to repeat these experiments and to investigate whether this compound labeled a single protein or multiple proteins. I realized that multiple proteins were labeled by [³H]flunitrazepam and that labeling by this compound could be stimulated by GABA and differentially inhibited by some compounds that had been claimed to exhibit some selectivity for benzodiazepine receptor subtypes. This work resulted in the first demonstration of a molecular heterogeneity of benzodiazepine receptors and indicated that all these receptors are associated with GABA_A receptors (Sieghart and Karobath, Nature 286: 285-287, 1980).

Unfortunately, at that time not many people had the excellent training in SDS-polyacrylamide gel electrophoresis techniques I had in Greengard’s lab, and thus, my work could not be repeated by other groups at first. This was quite embarrassing, and I spent the next years using a variety of approaches to demonstrate that my photolabeling data were correct and that there are multiple GABA_A receptors. Overall, I succeeded, but nevertheless I was quite happy when the first GABA_A receptor subunits were cloned in 1987 (Schofield et al., Nature 328: 221-227, 1987) and the first rumors spread that there probably are multiple GABA_A receptor subunits. At that time I summarized all evidence for the existence of a multiplicity of GABA_A receptors in a widely recognized review (Sieghart, TIPS 10: 407-411, 1989).

When multiple receptors do exist, it might be possible to differentially modulate them. Thus, from the very beginning I tried to find compounds with a differential affinity for the different GABA_A receptor subtypes as a strategy to demonstrate their existence. I succeeded in identifying the first benzodiazepines with some selectivity for GABA_A receptor subtypes (Sieghart, Neurosci. Letters 38: 73-78, 1983), but their selectivity was quite weak. Then I realized that a variety of other compounds might also interact with GABA_A receptors and summarized this evidence in another widely recognized review (Sieghart, TIPS 13: 446-450, 1992).

Based on these two TIPS reviews, I was invited to write a review article on "Structure and pharmacology of GABA_A receptor subtypes" in Critical Reviews in Pharmacology, a journal to be newly launched by CRC. I submitted this article at the end of 1993. At the beginning of 1994, I was told that the publication of this journal was canceled by CRC and that I could have included my review as a chapter in a CRC-published monograph. Since I had the feeling that this was an excellent review, I did not want to bury it in a monograph that would not be read and cited. I therefore withdrew my article from CRC and contacted Pharmacological Reviews on whether they were interested in a comprehensive review on this matter. This proposal was accepted after I had sent a curriculum vitae, a short bibliography and a detailed outline of the manuscript.

I reworked and updated the review and submitted it in the middle of April 1994. In the middle of July 1994 I received the comments of the referees. The referees were quite competent in the GABA_A receptor field. Although they liked the work, they also pointed to some weaknesses of the manuscript and made some very valuable suggestions that turned out to improve the paper substantially, especially to present all pharmacological data as tables and to extend the review to include a chapter on the plasticity of the receptors.

Overall, the suggestions of the reviewers precipitated a lot of work. I had to update the review, to compile all data for the extensive tables and to extend it by adding information on the plasticity of GABA_A receptors. It took more than six months to complete this revision. I submitted the revision in January 1995, and the review was finally accepted for publication.

I thus spent more than a year of pure working time in writing this review, but overall, it was worth it. In particular, the suggestion to compile all available data in tables was very valuable and represented a major advantage of this review over most previous reviews. I constantly use the tables from this review myself to refresh my knowledge on the pharmacology of GABA_A receptor subtypes, and I believe that these tables are the main reason why this review is highly cited. In a fast-moving field like the GABA_A receptors it is impossible to keep track on all the findings of the past years. Comprehensive and competent reviews are thus essential to provide easy access to the available knowledge.

Interestingly, not too much has changed in the knowledge on the structure and pharmacology of GABA_A receptor subtypes since this review has been published. Of course, new information is now available on the structure of the GABA_A receptors, new compounds have been synthesized with some selectivity for GABA_A receptor subtypes, and now for the first time the importance of various receptor subtypes for certain functions in the brain has been demonstrated. But overall, most of the information provided in this review still holds true, and the article still can be used as a reference when looking for certain information.

What can be expected in the next few years? I am quite confident that the GABA_A receptors will be crystallized within the next few years and that a multitude of information will be gained on the structure and function of these important receptors. In addition, I am quite confident that in the near future compounds with high subtype selectivity will be developed that will dramatically improve the treatment of various diseases. These compounds, however, will also provide possibilities for a more detailed study of the function of all these receptor subtypes in the brain. But this, for sure, is an exciting task for the next generation of researchers.