PREFACE A Tribute to Professor Hanns M€ohler Few scientists make such major contributions that their name is forever linked to a particular molecule, pathway, or theory. Professor Hanns M€ ohler is one of those individuals. Everyone working in the areas of γ-aminobutyric acid (GABA) neurochemistry and neuropharmacology is familiar with Hanns’ work and its importance in characterizing the GABAA receptor. While many made seminal contributions in defining this system, none can match Hanns in terms of groundbreaking discoveries and creative insights regarding the structure, function, and clinical importance of GABAA sites. Even a cursory glance through the literature reveals Hanns’ impact on neuropharmacology over the past four decades, his uncanny ability to sense the direction of the field, and his skills in adopting the techniques and technologies necessary for advancing the understanding of GABAergic transmission. Besides his contributions to the basic neurosciences, Hanns’ efforts in drug discovery led to significant clinical advances. It all began while he was working at Hoffmann-La Roche in Basel, Switzerland, where he defined the molecular mechanism of action of the benzodiazepines, drugs used extensively for the treatment of anxiety, sleep disorders, muscle spasms, seizures, and in anesthesia. Diazepam (ValiumR) is a prototype of this chemical class. Hanns’ work contributed greatly to identifying the benzodiazepine target as a component of the GABAA receptor. He and others demonstrated that when bound to this site the benzodiazepines enhance allosterically the activity of this major inhibitory neurotransmitter receptor system. His subsequent discovery of flumazenil (AnexateR), a benzodiazepine antagonist, was the direct result of his earlier findings, demonstrating the translational nature of his work and its practical clinical applications. Upon leaving Hoffmann-La Roche, Hanns established an academic laboratory at the University of Zurich, where he remains as Emeritus Professor. With his team at
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the University of Zurich, he established and categorized the distinct pharmacological functions of GABAA receptor subtypes. This information is proving critical for designing and developing the next generation of drugs as it makes possible the selective targeting of those GABAA receptors responsible for mediating anxiolysis while leaving untouched those responsible for sedation and effects on cognition. In addition to his work on the GABA system, Hanns developed strategies for exploiting adenosine as a treatment for epilepsy and glycine for dampening some symptoms of schizophrenia. These efforts underscore his dedication to identifying the clinical opportunities presented by discoveries in the basic neurosciences. Given these accomplishments, Hanns’ work has had a significant impact on the careers of countless neuroscientists and millions of patients. His legacy will always be tied to the critical role he played in defining the properties of the GABAA receptor, with his influence lingering for decades as his findings continue to be exploited for therapeutic gain. Hanns M€ ohler received his BA in Chemistry from the University of Bonn, his MA in Biochemistry from the University of T€ ubingen, and his Ph.D. in Biochemistry from the University of Freiburg in Germany. While pursuing his doctoral degree, he spent 18 months studying in the Department of Biochemistry at Michigan State University. His interest in the budding field of neuroscience led him to pursuing postdoctoral work at the Medical Research Council in London before accepting a research position at Hoffmann-La Roche in Basel. The Basel appointment was particularly attractive as it allowed him to pursue his passion for the neurosciences. During his time at Hoffmann-La Roche, he held academic appointments at the University of Freiburg, his alma mater. In 1988, Hanns was elected Professor of Pharmacology and Director of the Institute of Pharmacology on the Medical Faculty of the University of Zurich, with a joint appointment in the Department of Chemistry and Applied Biosciences at the Swiss Federal Institute of Technology (ETH) in Zurich. He was also the first Director of the Swiss National Center of Neuroscience Research where some 200 basic and clinical neuroscientists and bioengineers collaborate in the areas of synaptic plasticity and repair. Hanns is the recipient of a number of major awards in recognition of his research accomplishments. Included among them are the Prize of the Foundation Forum, Engelberg, Switzerland, the Wachter Prize for Medical Research from the University of Innsbruck, The Neuroscience Award of the European College of Neuropsychopharmacology, the Theodore-OttPrize, the most prestigious prize in Switzerland for a neuroscientist, from
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the Swiss Academy of Medical Sciences, and the Golden Kraepelin Medal from the Max-Planck-Institute of Psychiatry, Munich. He is an elected member of the European Academy of Sciences and an honorary member, and a member of the board, of the Swiss Academy of Medical Sciences. He has been appointed as a fellow of the Collegium Helveticum. He serves on the editorial boards of a number of leading journals in the fields of pharmacology and neurosciences. The impact of Hanns’ work is evident from his publication record. As of September 2014, PubMed listed 249 articles authored or coauthored by Hanns M€ ohler. Much of this work appears in Nature, Science, Nature Neuroscience, and the Proceedings of the National Academy of Sciences USA. Data published by Thomson Reuters indicate Hanns’ work has been cited 23,263 times, with an h-index of 80. He has been consistently listed by the Institute of Scientific Information among the “Highly Cited Researchers” in Neuroscience. In addition to his scientific discoveries, Hanns is recognized for his contributions to education in the field. Together with Kurt Jungermann, he coauthored a popular German biochemistry textbook and is routinely rated as an outstanding lecturer by students of medicine, pharmacy, pharmaceutical sciences, chemistry, and biology. He has mentored dozens of individuals in his laboratory, from research group leaders to visiting scientists, postdoctoral fellows, and graduate and undergraduate students. Many have gone on to successful, independent research careers, as evidenced by the authors contributing to these volumes. Volumes 72 and 73 of Advances in Pharmacology were prepared to honor Hanns M€ ohler and his work. Contributing authors were drawn from the universe of his scientific collaborators, colleagues, students, and fellows. All those invited eagerly agreed to participate in the creation of these volumes. While many of the chapters include sections highlighting the authors’ past associations with Hanns, the vast majority of the reports are devoted to describing the latest developments in the field. Given this design, the contents of these volumes provide not only historical perspectives on the development of GABAA pharmacology but also state-of-the-art research in the field and the promise for the future. Topics covered include the behavioral and pharmacological phenotypes of GABAA receptor subunit knockout and knockin mice animals and the effects of point mutations on the allosteric properties of this site. Other subjects include the role of glutamatergic neurons in the sedative actions of benzodiazepines, the role of GABAA receptors in substance abuse, and the mechanisms responsible for the development of
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tolerance to the benzodiazepines. Even this partial list of volume subjects indicates the breadth of Hanns’ interests and those of his associates. It also illustrates the productivity that results from working in a collegial, collaborative, and multidisciplinary environment, such as that provided by Hanns at the University of Zurich. It was an honor for us to work on the development of these volumes to recognize Hanns’ contributions to our discipline. Along with the other contributing authors, we are privileged to know such an accomplished scientist and scholar, and to have him as a colleague, collaborator, and mentor. Besides showing our respect for Hanns’ scientific insight, creativity, and productivity, we hope that these volumes will in some small way demonstrate our appreciation for the friendship, warmth, and encouragement he has so generously bestowed on each of us over the past 40 years. UWE RUDOLPH Laboratory of Genetic Neuropharmacology, McLean Hospital, Belmont, and Department of Psychiatry, Harvard Medical School, Boston, Massachusetts, USA S.J. ENNA Department of Molecular and Integrative Physiology, Department of Pharmacology, Toxicology and Therapeutics, University of Kansas Medical Center, Kansas City, Kansas, USA
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the University of Zurich, he established and categorized the distinct pharmacological functions of GABAA receptor subtypes. This information is proving critical for designing and developing the next generation of drugs as it makes possible the selective targeting of those GABAA receptors responsible for mediating anxiolysis while leaving untouched those responsible for sedation and effects on cognition. In addition to his work on the GABA system, Hanns developed strategies for exploiting adenosine as a treatment for epilepsy and glycine for dampening some symptoms of schizophrenia. These efforts underscore his dedication to identifying the clinical opportunities presented by discoveries in the basic neurosciences. Given these accomplishments, Hanns’ work has had a significant impact on the careers of countless neuroscientists and millions of patients. His legacy will always be tied to the critical role he played in defining the properties of the GABAA receptor, with his influence lingering for decades as his findings continue to be exploited for therapeutic gain. Hanns M€ ohler received his BA in Chemistry from the University of Bonn, his MA in Biochemistry from the University of T€ ubingen, and his Ph.D. in Biochemistry from the University of Freiburg in Germany. While pursuing his doctoral degree, he spent 18 months studying in the Department of Biochemistry at Michigan State University. His interest in the budding field of neuroscience led him to pursuing postdoctoral work at the Medical Research Council in London before accepting a research position at Hoffmann-La Roche in Basel. The Basel appointment was particularly attractive as it allowed him to pursue his passion for the neurosciences. During his time at Hoffmann-La Roche, he held academic appointments at the University of Freiburg, his alma mater. In 1988, Hanns was elected Professor of Pharmacology and Director of the Institute of Pharmacology on the Medical Faculty of the University of Zurich, with a joint appointment in the Department of Chemistry and Applied Biosciences at the Swiss Federal Institute of Technology (ETH) in Zurich. He was also the first Director of the Swiss National Center of Neuroscience Research where some 200 basic and clinical neuroscientists and bioengineers collaborate in the areas of synaptic plasticity and repair. Hanns is the recipient of a number of major awards in recognition of his research accomplishments. Included among them are the Prize of the Foundation Forum, Engelberg, Switzerland, the Wachter Prize for Medical Research from the University of Innsbruck, The Neuroscience Award of the European College of Neuropsychopharmacology, the Theodore-OttPrize, the most prestigious prize in Switzerland for a neuroscientist, from
Preface
xi
the Swiss Academy of Medical Sciences, and the Golden Kraepelin Medal from the Max-Planck-Institute of Psychiatry, Munich. He is an elected member of the European Academy of Sciences and an honorary member, and a member of the board, of the Swiss Academy of Medical Sciences. He has been appointed as a fellow of the Collegium Helveticum. He serves on the editorial boards of a number of leading journals in the fields of pharmacology and neurosciences. The impact of Hanns’ work is evident from his publication record. As of September 2014, PubMed listed 249 articles authored or coauthored by Hanns M€ ohler. Much of this work appears in Nature, Science, Nature Neuroscience, and the Proceedings of the National Academy of Sciences USA. Data published by Thomson Reuters indicate Hanns’ work has been cited 23,263 times, with an h-index of 80. He has been consistently listed by the Institute of Scientific Information among the “Highly Cited Researchers” in Neuroscience. In addition to his scientific discoveries, Hanns is recognized for his contributions to education in the field. Together with Kurt Jungermann, he coauthored a popular German biochemistry textbook and is routinely rated as an outstanding lecturer by students of medicine, pharmacy, pharmaceutical sciences, chemistry, and biology. He has mentored dozens of individuals in his laboratory, from research group leaders to visiting scientists, postdoctoral fellows, and graduate and undergraduate students. Many have gone on to successful, independent research careers, as evidenced by the authors contributing to these volumes. Volumes 72 and 73 of Advances in Pharmacology were prepared to honor Hanns M€ ohler and his work. Contributing authors were drawn from the universe of his scientific collaborators, colleagues, students, and fellows. All those invited eagerly agreed to participate in the creation of these volumes. While many of the chapters include sections highlighting the authors’ past associations with Hanns, the vast majority of the reports are devoted to describing the latest developments in the field. Given this design, the contents of these volumes provide not only historical perspectives on the development of GABAA pharmacology but also state-of-the-art research in the field and the promise for the future. Topics covered include the behavioral and pharmacological phenotypes of GABAA receptor subunit knockout and knockin mice animals and the effects of point mutations on the allosteric properties of this site. Other subjects include the role of glutamatergic neurons in the sedative actions of benzodiazepines, the role of GABAA receptors in substance abuse, and the mechanisms responsible for the development of
xii
Preface
tolerance to the benzodiazepines. Even this partial list of volume subjects indicates the breadth of Hanns’ interests and those of his associates. It also illustrates the productivity that results from working in a collegial, collaborative, and multidisciplinary environment, such as that provided by Hanns at the University of Zurich. It was an honor for us to work on the development of these volumes to recognize Hanns’ contributions to our discipline. Along with the other contributing authors, we are privileged to know such an accomplished scientist and scholar, and to have him as a colleague, collaborator, and mentor. Besides showing our respect for Hanns’ scientific insight, creativity, and productivity, we hope that these volumes will in some small way demonstrate our appreciation for the friendship, warmth, and encouragement he has so generously bestowed on each of us over the past 40 years. UWE RUDOLPH Laboratory of Genetic Neuropharmacology, McLean Hospital, Belmont, and Department of Psychiatry, Harvard Medical School, Boston, Massachusetts, USA S.J. ENNA Department of Molecular and Integrative Physiology, Department of Pharmacology, Toxicology and Therapeutics, University of Kansas Medical Center, Kansas City, Kansas, USA
