title: Endozepines.
abstract: Since their introduction in the 1960s, benzodiazepines (BZs) remain one of the most commonly prescribed medications, acting as potent sedatives, hypnotics, anxiolytics, anticonvulsants, and muscle relaxants. The primary neural action of BZs and related compounds is augmentation of inhibitory transmission, which occurs through allosteric modulation of the gamma-aminobutyric acid (GABA)-induced current at the gamma-aminobutyric acid receptor (GABAAR). The discovery of the BZ-binding site on GABAARs encouraged many to speculate that the brain produces its own endogenous ligands to this site (Costa & Guidotti, 1985). The romanticized quest for endozepines, endogenous ligands to the BZ-binding site, has uncovered a variety of ligands that might fulfill this role, including oleamides (Cravatt et al., 1995), nonpeptidic endozepines (Rothstein et al., 1992), and the protein diazepam-binding inhibitor (DBI) (Costa & Guidotti, 1985). Of these ligands, DBI, and affiliated peptide fragments, is the most extensively studied endozepine. The quest for the "brain's Valium" over the decades has been elusive as mainly negative allosteric modulatory effects have been observed (Alfonso, Le Magueresse, Zuccotti, Khodosevich, & Monyer, 2012; Costa & Guidotti, 1985), but recent evidence is accumulating that DBI displays regionally discrete endogenous positive modulation of GABA transmission through activation of the BZ receptor (Christian et al., 2013). Herein, we review the literature on this topic, focusing on identification of the endogenous molecule and its region-specific expression and function.
authors.affiliation: Department of Neurology and Neurological Sciences, Stanford University School of Medicine, Stanford, California, USA.
authors.forename: Zoya
authors.initials: Z
authors.lastname: Farzampour
authors.affiliation: Department of Neurology and Neurological Sciences, Stanford University School of Medicine, Stanford, California, USA; Graduate Program in Neuroscience, Stanford University School of Medicine, Stanford, California, USA; Neurology Service, Veterans Affairs Palo Alto Health Care System, Palo Alto, California, USA.
authors.forename: Richard J
authors.initials: RJ
authors.lastname: Reimer
authors.affiliation: Department of Neurology and Neurological Sciences, Stanford University School of Medicine, Stanford, California, USA; Graduate Program in Neuroscience, Stanford University School of Medicine, Stanford, California, USA. Electronic address: john.huguenard@stanford.edu.
authors.forename: John
authors.initials: J
authors.lastname: Huguenard
mesh_terms: D000494:Allosteric Regulation; D000818:Animals; D001569:Benzodiazepines / Q000494:pharmacology; D001665:Binding Sites; D001921:Brain / Q000378:metabolism; D026261:Diazepam Binding Inhibitor / Q000378:metabolism*; D006801:Humans; D008024:Ligands; D011963:Receptors, GABA-A / Q000187:drug effects / Q000378:metabolism*; D005680:gamma-Aminobutyric Acid / Q000378:metabolism*
chemical_list: D026261:Diazepam Binding Inhibitor; D008024:Ligands; D011963:Receptors, GABA-A; D001569:Benzodiazepines; D005680:gamma-Aminobutyric Acid
keywords: Acyl-CoA-binding protein; Allosteric; Benzodiazepine; Diazepam-binding inhibitor; Endogenous ligand; Epilepsy; GABA; GABA(A) receptors