Barbiturate activation and modulation of GABAA receptors in neocortex

We determined if anesthetic and anti-epileptic barbiturates inhibit neurons by different mechanisms. Current- and voltage-clamp recordings were made from somatosensory neurons of neocortex and some thalamocortical neurons in coronal brain slices of rats. We compared effects of pentobarbital, amobarbital, and phenobarbital on inhibitory postsynaptic currents (IPSCs) mediated by γ-aminobutyric acid (GABA), input conductance, and evoked action potential firing. In neocortex, pentobarbital (EC50 = 41 μM) and amobarbital (EC50 = 103 μM) increased the decay time constant of GABAAergic IPSCs. At higher concentrations, pentobarbital and amobarbital shunted firing by increasing input conductance through agonism at GABAA receptors. At anti-epileptic concentrations, phenobarbital increased the IPSC decay time constant (EC50 = 144 μM), and shunted firing by agonism at GABAA receptors (EC50 = 133 μM). In thalamocortical neurons, similar concentrations of phenobarbital had negligible effects on GABAAergic IPSCs, conductance, and firing. In contrast to their thalamic actions, barbiturates inhibit neocortical neurons mostly through GABA receptors. Neocortical enhancement of inhibition by pentobarbital and amobarbital, combined with actions on thalamocortical neurons, may contribute to redundant mechanisms of anesthesia. The ability of phenobarbital at anti-epileptic concentrations to inhibit neocortical firing by direct activation and modulation of GABAA receptors relates to its specialized therapeutic effects.