Awardee 2001

Hanns Möhler

for the Elucidation of the effects of Benzodiazepines on brain function

The regulation of brain function by a major group of psychoactive drugs, the benzodiazepines, is the central theme of the scientific work of Hanns Möhler. His studies are highly interdisciplinary, encompass all levels of biological organization from the genetic to the behavioral level and excel by fundamental discoveries.

Benzodiazepines are among the most widely used drugs worldwide. Unraveling their mechanism of action is a landmark in the history of psychopharmacology, pioneered to an essential part by Hanns Möhler. He not only co-authored the original GABA hypothesis for the action of benzodiazepines but identified their molecular target in the brain in a seminal paper, which has become a citation classic. The so-called benzodiazepine receptor was identified by him not only as a radioligand-binding site but also - by photoaffinity labeling- as a protein. He succeeded in locating this receptor protein in identified GABAergic synapses. The protein was the first identified component of the GABAA-receptor.

Hanns Möhler changed our view of GABAergic transmission. Originally considered to be a rather unified type of transmission he visualized a genetic program in neurons permitting them to generate a wide variety of GABAA-receptor subtypes based on different subunit complements. Using highly advanced immunohistochemical techniques he identified the first five GABAA-receptor subtypes in situ and showed the distinctive features of their channel function in recombinant receptor systems. The newly discovered GABAA-receptor heterogeneity introduced a distinctive synaptic marker into GABAergic neurotransmission.

A deficit of GABAA-receptors is frequently seen by positron emission tomography (PET) in patients with panic anxiety. In an animal model Hanns Möhler was able to identify the molecular deficit of GABAA-receptor as a contributor to anxiety behavior. The animal model was generated by reducing the synaptic clustering of GABAA-receptors. This was achieved in a mouse line heterozygous for the gamma 2-subunit which anchors the GABAA-receptor to the postsynaptic cytoskeleton. Behaviorally, only anxiety responses were enhanced including a cognitive bias for threat cues, which is a hallmark of anxiety symptoms in humans. Thus, by the genetic alteration of GABAA-receptor clustering the brain was set to operate in an anxiety mode. The underlying alterations in neuronal circuits can now be studied as well as their mode of interaction with the environment. Furthermore, the study points to potential candidate genes for a genetic basis of anxiety disorders in humans.

The contribution of Hanns Möhler to drug development was first highlighted by the discovery of flumazenil, which is now in clinical use as benzodiazepine antagonist. This compound is also the preferred ligand for PET imaging of GABAA-receptors in various disease states. Recently he opened up an entirely new realm for a rational drug development ending a 30-year period of heuristic search for improved ligands acting at the benzodiazepine site. GABAA-receptor subtypes have long been considered as promising goals for drug development. However it was only recently that the pharmacological function of GABAA-receptor subtypes was identified. This was achieved with an ingenious point mutation methodology. By introducing a single point mutation in the benzodiazepine-binding site, specific GABAA-receptor subtypes where rendered diazepam insensitive in vivo. The drug action mediated by the corresponding receptor was expected to be absent in the pharmacology of the point-mutated mouse. This strategy was implemented by generating mouse lines in which the a1-, a2- and a3-GABAA-receptors were selectively point mutated by converting a conserved histidine residue into arginine. The genetic selection markers (neomycin cassette) were removed from the genome to avoid a potential interference in the phenotype. Furthermore, it was demonstrated that the point mutation did not interfere with the synthesis, assembly and location of the GABAA-receptors. Finally, it was assured that the GABA-induced gating of the channel in vivo was unimpaired by the point mutation.

In an outstanding series of publications Hanns Möhler identified the a1-GABAA-receptors as mediators of the sedative, anticonvulsant and anterograde amnesic actions of benzodiazepines. In addition the small population of a2-GABAA-receptors was found to mediate the anxiolytic activity of benzodiazepines. This result was in keeping with the location of a2-GABA-receptors in areas closely linked to the processing of emotional stimuli. a2-GABAA-receptors are highly expressed in the central nucleus of the amygdala and are densely packed on the axon initial segment of the principal cells in the cerebral cortex and hippocampus where they control their output activity. Thus, a new pharmacology for benzodiazepine site ligands is on the horizon. The classical spectrum of benzodiazepines and their side effects will be dissected by the development of ligands selective for GABAA-receptor subtypes. In addition, drug elicited at selective GABAA-receptors can be envisaged to go beyond those of the classical benzodiazepines.

  Study of Chemistry and Biochemistry at the Universities of Bonn, Tübingen and Freiburg
1968 PhD of Biochemistry (Freiburg)
1967-1968 Guest Scientist/Professor at Michigan State University
1968-1971 University of Freiburg
1972-1973 Medical Research Council London - Senior Research Scientist
1973-1988 Research Department Hoffmann-La Roche Basel - Department Director and Vice-Director
  Member of several Swiss and International Research Review Committees
  Recipient of numerous academic Honours and Awards
Most important scientific achievements:
  Discovery of the benzodiazepin receptor and of the GABA receptor heterogeneity
  Elucidation of the mechanism of action of the benzodiazepins
  Key role in the discovery of the benzodiazepin antagonist flumenazil
  Discovery of the role of deficient GABA receptors as a genetic factor of anxiety reactions
  Description of neuronal circuits for the regulation of emotions
  Establishment of a single point mutation technique for drug modelling, i.e. for the development of specific ligands for GABA receptor subtypes