Joyce Besheer1, Veronique Lepoutre, Clyde W Hodge. 1. Bowles Center for Alcohol Studies, Department of Psychiatry, Thurston-Bowles Building, University of North Carolina at Chapel Hill, CB#7178, Chapel Hill, NC 27599, USA. jbesheer@med.unc.edu
Abstract
RATIONALE: A growing number of studies suggest that gamma-aminobutyric acid type-B (GABA(B)) receptor agonists reduce alcohol use and craving. OBJECTIVES: This study was designed to further clarify behavioral mechanism(s) by which GABA(B) agonists may decrease alcohol reinforcement. METHODS: Male C57BL/6 J mice were trained to lever press on a concurrent schedule of ethanol (10% v/v) and water reinforcement during 16-h overnight sessions. Effects of the GABA(B) agonist baclofen (0-17 mg/kg, IP) or SKF 97541 (0-1 mg/kg, IP) were examined on parameters of self-administration. Subsequently, potential motor inhibition and interaction with ethanol-induced sedation by GABA(B) agonists was examined in ethanol naive and self-administering mice. RESULTS: Baclofen (10 mg/kg) and SKF 97541 (0.3 mg/kg) reduced ethanol-reinforced responding. In a locomotor activity test, these doses of the GABA(B) agonists inhibited locomotion in the ethanol-experienced mice and in a group of ethanol-inexperienced mice; locomotor suppression was greater in the ethanol-inexperienced mice. These doses of the GABA(B) agonists also potentiated the sedative effects of ethanol (4 g/kg) and converted a nonsedative dose of ethanol (2 g/kg) into a fully sedative dose. GABA(B) agonist enhancement of the sedative effects of ethanol was less pronounced in ethanol self-administering mice, suggesting cross-tolerance at the low dose of ethanol. CONCLUSIONS: GABA(B) agonists decrease the reinforcing effects of ethanol at doses that inhibit locomotor activity and potentiate the sedative hypnotic effects of ethanol. These nonspecific effects of GABA(B) agonists were reduced in alcohol experienced mice, suggesting cross-tolerance to the inhibitory properties of GABA(B) positive modulation. These data question the safety of prescribing GABA(B) agonists to alcoholics since these drugs may potentiate ethanol's sedative/hypnotic effects during relapse.
RATIONALE: A growing number of studies suggest that gamma-aminobutyric acid type-B (GABA(B)) receptor agonists reduce alcohol use and craving. OBJECTIVES: This study was designed to further clarify behavioral mechanism(s) by which GABA(B) agonists may decrease alcohol reinforcement. METHODS: Male C57BL/6 J mice were trained to lever press on a concurrent schedule of ethanol (10% v/v) and water reinforcement during 16-h overnight sessions. Effects of the GABA(B) agonist baclofen (0-17 mg/kg, IP) or SKF 97541 (0-1 mg/kg, IP) were examined on parameters of self-administration. Subsequently, potential motor inhibition and interaction with ethanol-induced sedation by GABA(B) agonists was examined in ethanol naive and self-administering mice. RESULTS:Baclofen (10 mg/kg) and SKF 97541 (0.3 mg/kg) reduced ethanol-reinforced responding. In a locomotor activity test, these doses of the GABA(B) agonists inhibited locomotion in the ethanol-experienced mice and in a group of ethanol-inexperienced mice; locomotor suppression was greater in the ethanol-inexperienced mice. These doses of the GABA(B) agonists also potentiated the sedative effects of ethanol (4 g/kg) and converted a nonsedative dose of ethanol (2 g/kg) into a fully sedative dose. GABA(B) agonist enhancement of the sedative effects of ethanol was less pronounced in ethanol self-administering mice, suggesting cross-tolerance at the low dose of ethanol. CONCLUSIONS:GABA(B) agonists decrease the reinforcing effects of ethanol at doses that inhibit locomotor activity and potentiate the sedative hypnotic effects of ethanol. These nonspecific effects of GABA(B) agonists were reduced in alcohol experienced mice, suggesting cross-tolerance to the inhibitory properties of GABA(B) positive modulation. These data question the safety of prescribing GABA(B) agonists to alcoholics since these drugs may potentiate ethanol's sedative/hypnotic effects during relapse.
Authors: Giancarlo Colombo; Salvatore Serra; Giuliana Brunetti; Giuliana Atzori; Marialaura Pani; Giovanni Vacca; Giovanni Addolorato; Wolfgang Froestl; Mauro A M Carai; Gian Luigi Gessa Journal: Alcohol Alcohol Date: 2002 Sep-Oct Impact factor: 2.826
Authors: Giovanni Addolorato; Lorenzo Leggio; Ludovico Abenavoli; Fabio Caputo; Giovanni Gasbarrini Journal: Psychopharmacology (Berl) Date: 2004-09-30 Impact factor: 4.530
Authors: Clyde W Hodge; Michael F Miles; Amanda C Sharko; Rebekah A Stevenson; Jennie R Hillmann; Veronique Lepoutre; Joyce Besheer; Jason P Schroeder Journal: Psychopharmacology (Berl) Date: 2005-11-15 Impact factor: 4.530
Authors: Eric Augier; Russell S Dulman; Ruslan Damadzic; Andrew Pilling; J Paul Hamilton; Markus Heilig Journal: Neuropsychopharmacology Date: 2017-03-15 Impact factor: 7.853