Molecular interactions of ethanol with GABAergic system and potential of RO15-4513 as an ethanol antagonist

The behavioral and biochemical effects of ethanol in man and animals have been investigated for a long time. A role of catecholamines in the central stimulatory action and during withdrawal has been envisaged, but more recent observations have revealed the involvement of inhibitory synaptic transmitter, GABA, in the actions of ethanol. Ethanol-induced motor incoordination, hypnosedation, antianxiety, and anticonvulsant actions are reported to be GABA-mediated. Involvement of the GABA system has been implicated in ethanol withdrawal-induced seizures in animals. More direct evidences using Cl- influx studies in synaptoneurosomes and spinal neuronal culture studies confirm such a mode of action of ethanol, probably influencing the chloride channel modulation at the GABA-benzodiazepine receptor ionophore complex. RO15-4513 (ethyl-8-azido-5,6-dihydro-5-methyl-6-Oxo-4H-imidazo [1,5-alpha], [1,4] benzodiazepine-3-carboxylate), a novel imidazobenzodiazepine, an analogue of the classical benzodiazepine antagonist is reported to possess alcohol antagonistic properties. RO15-4513 reverses both the behavioral and biochemical effects of ethanol, including the action of GABA-induced Cl- fluxes. But its potential clinical application may be restricted due to its inverse agonistic property. The present review focuses on the GABA-linked behavioral and biochemical actions of ethanol and discusses the potential of RO15-4513 as an alcohol antagonist.