GABA α6 receptors mediate midazolam-induced anxiolysis

Study Objective: To compare the ability of midazolam to produce sedation and anxiolysis and attenuate memory in 100 patients aged 20 to 70 years. The effect of a point mutation (Pro385Ser) for the gamma amino-butyric acid (GABA) alpha6 receptor on the sedative, anxiolytic, and memory effects of midazolam was determined. Setting: University hospital. Design: Prospective, randomized, double-blind study, Patients: 100 ASA physical status I and II patients scheduled for surgery. Interventions: Two midazolam dose groups, 20 mug/kg and 40 mug/kg, with 40 patients per group and 20 control patients receiving saline as a sham control. Treatments were randomly assigned. Blood was collected at the beginning of each study. Measurements: Patient sedation and anxiolysis were measured using a visual analog scale and explicit and implicit memory of a word tash determined before and six minutes after midazolam or saline. A 365-base pair fragment of the GABA alpha6 receptor gene was amplified by polymerase chain reaction. (PCR) from, patient blood DNA and digested with the restrictase Fok I. Restriction fragments were visualized by ethidium bromide staining after electrophoresis to evaluate the GABA alpha6 receptor subunit mutation. Main Results: Midazolam produced dose-related sedation and anxiolysis. Explicit (recall) memory was attenuated with high-dose midazolam but implicit (recognition) memory remained intact. The GABA alpha6 receptor mutation did not affect baseline sedation, anxiety, or memory but significantly attenuated the anxiolytic affect of low-dose midazolam. Sedation and explicit memory were not affected by the mutation. Conclusions: A Pro385Ser mutation of the GABA alpha6 receptor subunit decreased the anxiolytic effect of low-dose midazolam. (C) 2002 by Elsevier Science Inc.