RATIONALE: A recent in-vitro study demonstrated that the potent disulfide reducing agent, DL-dithiothreitol (DTT), may alter the structural stability of the GABA(B) receptor, probably inactivating the disulfide bonds between four cysteine residues located in the GABA(B1(a)) receptor structure. OBJECTIVES: The present study was designed to evaluate whether DTT treatment was capable of antagonizing some behavioral effects of pharmacological stimulation of the GABA(B) receptor. METHODS: Experiments on sedation/hypnosis induced by the GABA(B) receptor agonists baclofen, SKF 97541, CGP 44532 and gamma-hydroxybutyric acid (GHB) in DBA mice and selectively bred GHB-sensitive (GHB-S) rats, and a GHB drug discrimination study in Long Evans rats were conducted. Specificity of the DTT action on the GABA(B) receptor was investigated by assessing its effect on the sedative/hypnotic effect induced by diazepam, ketamine and ethanol. RESULTS: DTT prevented the sedative/hypnotic effect of all GABA(B) receptor agonists tested and also reversed baclofen-induced sedation/hypnosis. In contrast, DTT had no effect on, or even potentiated, sedation/hypnosis produced by diazepam, ketamine or ethanol. DTT completely blocked the discriminative stimulus effects of GHB. CONCLUSIONS: These results are discussed in terms of DTT altering the stability of the binding domain of the GABA(B) receptor, hindering the drug-receptor interaction.
RATIONALE: A recent in-vitro study demonstrated that the potent disulfide reducing agent, DL-dithiothreitol (DTT), may alter the structural stability of the GABA(B) receptor, probably inactivating the disulfide bonds between four cysteine residues located in the GABA(B1(a)) receptor structure. OBJECTIVES: The present study was designed to evaluate whether DTT treatment was capable of antagonizing some behavioral effects of pharmacological stimulation of the GABA(B) receptor. METHODS: Experiments on sedation/hypnosis induced by the GABA(B) receptor agonists baclofen, SKF 97541, CGP 44532 and gamma-hydroxybutyric acid (GHB) in DBA mice and selectively bred GHB-sensitive (GHB-S) rats, and a GHB drug discrimination study in Long Evans rats were conducted. Specificity of the DTT action on the GABA(B) receptor was investigated by assessing its effect on the sedative/hypnotic effect induced by diazepam, ketamine and ethanol. RESULTS:DTT prevented the sedative/hypnotic effect of all GABA(B) receptor agonists tested and also reversed baclofen-induced sedation/hypnosis. In contrast, DTT had no effect on, or even potentiated, sedation/hypnosis produced by diazepam, ketamine or ethanol. DTT completely blocked the discriminative stimulus effects of GHB. CONCLUSIONS: These results are discussed in terms of DTT altering the stability of the binding domain of the GABA(B) receptor, hindering the drug-receptor interaction.
Authors: N G Bowery; B Bettler; W Froestl; J P Gallagher; F Marshall; M Raiteri; T I Bonner; S J Enna Journal: Pharmacol Rev Date: 2002-06 Impact factor: 25.468
Authors: M A Carai; G Colombo; G Brunetti; S Melis; S Serra; G Vacca; S Mastinu; A M Pistuddi; C Solinas; G Cignarella; G Minardi; G L Gessa Journal: Eur J Pharmacol Date: 2001-10-12 Impact factor: 4.432
Authors: C Lobina; G Colombo; G Brunetti; G Diaz; S Melis; M Pani; S Serra; G Vacca; G L Gessa; M A Carai Journal: Brain Res Brain Res Protoc Date: 2001-08
Authors: K Kaupmann; K Huggel; J Heid; P J Flor; S Bischoff; S J Mickel; G McMaster; C Angst; H Bittiger; W Froestl; B Bettler Journal: Nature Date: 1997-03-20 Impact factor: 49.962