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 SP - 226 LP - 235 DO - 10.1124/mol.112.078154 VL - 82 IS - 2 AU - Bridget L. Morse AU - Nisha Vijay AU - Marilyn E. Morris Y1 - 2012/08/01 UR - http://molpharm.aspetjournals.org/content/82/2/226.abstract N2 - Overdose of γ-hydroxybutyrate (GHB) frequently causes 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, (2S)-(+)-5,5-dimethyl-2-morpholineacetic acid (SCH50911), and a specific GABAA receptor antagonist, bicuculline, were administered before GHB. The potential therapeutic strategies of receptor inhibition and monocarboxylate transporter (MCT) inhibition were assessed by inhibitor administration 5 min 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 plus l-lactate further improved respiratory rate compared with the same dose of either agent alone, indicating that GABAB and MCT inhibitors, alone and in combination, represent potential treatment options for GHB-induced respiratory depression. ER -