Reduced side effect liability of novel β‐subunit selective GABAA receptor allosteric modulators

Abstract

Current benzodiazepine (BZ) anxiolytics, including diazepam, have well‐known side effects including sedation, memory impairment, abuse‐liability, withdrawal and limited tolerance (Kaplan and DuPont, 2005). We have previously characterized β‐subunit selective GABAA receptor (GABAARs) positive allosteric modulators (PAMs) as anxiolytics with a reduced sedative liability (Gee et al., 2010). Additional testing of the prototypical compound, UCI2‐261, a GABAAR β‐subunit selective anxiolytic, in a number of behavioral models reveal differences between it and typical agonist BZs. Unlike diazepam (2.5 mg/kg i.p.), UCI2‐261 (100 mg/kg, i.p.) does not have a significant amnestic effect in adult, male Sprague‐Dawley rats as measured by the eight‐arm radial arm maze. Furthermore, subchronic (7 days, q.d.) treatment of adult, male CD‐1 mice with UCI2‐261 (10 mg/kg, i.p.) does not induce tolerance to its anxiolytic effect in the elevated plus maze. These results suggest that β‐subunit selective GABAAR PAMs not only have reduced sedative‐liability, but may not share other side effects commonly associated with agonist BZs.