title: The legacy of the benzodiazepine receptor: from flumazenil to enhancing cognition in Down syndrome and social interaction in autism.
abstract: The study of the psychopharmacology of benzodiazepines continues to provide new insights into diverse brain functions related to vigilance, anxiety, mood, epileptiform activity, schizophrenia, cognitive performance, and autism-related social behavior. In this endeavor, the discovery of the benzodiazepine receptor was a key event, as it supplied the primary benzodiazepine drug-target site, provided the molecular link to the allosteric modulation of GABAA receptors and, following the recognition of GABAA receptor subtypes, furnished the platform for future, more selective drug actions. This review has two parts. In a retrospective first part, it acknowledges the contributions to the field made by my collaborators over the years, initially at Hoffmann-La Roche in Basle and later, in academia, at the University and the ETH of Zurich. In the second part, the new frontier of GABA pharmacology, targeting GABAA receptor subtypes, is reviewed with special focus on nonsedative anxiolytics, antidepressants, analgesics, as well as enhancers of cognition in Down syndrome and attenuators of symptoms of autism spectrum disorders. It is encouraging that a clinical trial has been initiated with a partial inverse agonist acting on α5 GABAA receptors in an attempt to alleviate the cognitive deficits in Down syndrome.
authors.affiliation: Institute of Pharmacology and Toxicology, University of Zurich, Zurich, Switzerland; Department of Chemistry and Applied Biosciences, Federal Institute of Technology (ETH), Zurich, Switzerland. Electronic address: mohler@pharma.uzh.ch.
authors.forename: Hanns
authors.initials: H
authors.lastname: Möhler
mesh_terms: D000818:Animals; D014151:Anti-Anxiety Agents / Q000494:pharmacology; D001321:Autistic Disorder / Q000188:drug therapy / Q000503:physiopathology; D001569:Benzodiazepines / Q000494:pharmacology*; D003071:Cognition / Q000187:drug effects; D004314:Down Syndrome / Q000188:drug therapy / Q000503:physiopathology; D005442:Flumazenil / Q000494:pharmacology; D018757:GABA Modulators / Q000494:pharmacology*; D006801:Humans; D007398:Interpersonal Relations; D011963:Receptors, GABA-A / Q000187:drug effects* / Q000378:metabolism
chemical_list: D014151:Anti-Anxiety Agents; D018757:GABA Modulators; D011963:Receptors, GABA-A; D001569:Benzodiazepines; D005442:Flumazenil
keywords: Analgesics; Anxiolytics; Benzodiazepines; Cognitive dysfunction; Depression