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Updated: Aug 29, 2026

Methods for the Discovery of Novel Compounds Modulating a Gamma-Aminobutyric Acid Receptor Type A Neurotransmission
Published on: August 16, 2018
Suppression of GABA(B) receptor function in vivo by disulfide reducing agent, DL-dithiothreitol (DTT)
Mauro A M Carai1, Giovanni Vacca, Salvatore Serra
1Bernard B. Brodie Department of Neuroscience, University of Cagliari, Viale Diaz 182, 09126 Cagliari, Italy. caraimam@tiscali.it
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.
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