Affinities of barbiturates for the GABA-receptor complex and A1 adenosine receptors: a possible explanation of their excitatory effects.

The effects of barbiturates on the GABA-receptor complex and the A1 adenosine receptor were studied. At the GABA-receptor complex the barbiturates inhibited the binding of [35S]t-butylbicyclophosphorothionate ([35S]TBPT) and enhanced the binding of [3H]diazepam. Kinetic and saturation experiments showed that both effects were allosteric. Whereas all barbiturates caused complete inhibition of [35S]TBPT binding, they showed varying degrees of maximal enhancement of [3H]diazepam binding; (+/-)methohexital was identified as the most efficacious compound for this enhancement. At the A1 adenosine receptor all barbiturates inhibited the binding of [3H]N6-phenylisopropyladenosine ([3H]PIA) in a competitive manner. The comparison of the effects on [3H]diazepam and [3H]PIA binding showed that excitatory barbiturates interact preferentially with the A1 adenosine receptor, and sedative/anaesthetic barbiturates with the GABA-receptor complex. It is speculated that the interaction with these two receptors might be the basis of the excitatory versus sedative/anaesthetic properties of barbiturates.