TY - JOUR T1 - γ-hydroxybutyrate (GHB)-Induced Respiratory Depression: Combined Receptor-Transporter Inhibition Therapy for Treatment in GHB Overdose JF - Molecular Pharmacology JO - Mol Pharmacol DO - 10.1124/mol.112.078154 SP - mol.112.078154 AU - Bridget L Morse AU - Nisha Vijay AU - Marilyn E. Morris Y1 - 2012/05/04 UR - http://molpharm.aspetjournals.org/content/early/2012/05/04/mol.112.078154.abstract N2 - Overdose of γ-hydroxybutyrate (GHB) frequently results in respiratory depression, occasionally resulting in death; however, little is known about the dose-response relationship or effects of potential overdose treatment strategies on GHB-induced respiratory depression. In these studies, the parameters of respiratory rate, tidal volume, and minute volume were measured using whole-body plethysmography in rats administered GHB. Intravenous doses of 200, 600, and 1500 mg/kg were administered to assess the dose-dependent effects of GHB on respiration. To determine the receptors involved in GHB-induced respiratory depression, a specific GABAB receptor antagonist, SCH50911 ((2S)-(+)-5,5-dimethyl-2-morpholineacetic acid), and a specific GABAA receptor antagonist, bicuculline, were administered prior to GHB. The potential therapeutic strategies of receptor inhibition and monocarboxylate transporter (MCT) inhibition were assessed by inhibitor administration 5 minutes after GHB. The primary effect of GHB on respiration was a dose-dependent decrease in respiratory rate, accompanied by an increase in tidal volume, resulting in little change in minute volume. Pretreatment with 150 mg/kg SCH50911 completely prevented the decrease in respiratory rate, indicating agonism at GABAB receptors to be primarily responsible for GHB-induced respiratory depression. Administration of 50 mg/kg SCH50911 after GHB completely reversed the decrease in respiratory rate; lower doses had partial effects. Administration of the MCT inhibitor L-lactate increased GHB renal and total clearance, also improving respiratory rate. Administration of 5 mg/kg SCH50911 + L-lactate further improved respiratory rate compared to the same dose of either agent alone, indicating GABAB and MCT inhibition, alone and in combination, to represent potential therapeutic strategies for treating GHB-induced respiratory depression. ER -