Suppression of GABAB receptor function in vivo by disulfide reducing agent, DL-dithiothreitol (DTT)

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.