Barbiturate activation and modulation of GABA(A) 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 gamma-aminobutyric acid (GABA), input conductance, and evoked action potential firing. In neocortex, pentobarbital (EC(50)=41 microM) and amobarbital (EC(50)=103 microM) increased the decay time constant of GABA(A)ergic IPSCs. At higher concentrations, pentobarbital and amobarbital shunted firing by increasing input conductance through agonism at GABA(A) receptors. At anti-epileptic concentrations, phenobarbital increased the IPSC decay time constant (EC(50)=144 microM), and shunted firing by agonism at GABA(A) receptors (EC(50)=133 microM). In thalamocortical neurons, similar concentrations of phenobarbital had negligible effects on GABA(A)ergic 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 GABA(A) receptors relates to its specialized therapeutic effects.
Mathers
David A
DA
Department of Cellular and Physiological Sciences, Faculty of Medicine, University of British Columbia, Vancouver, B.C. V6T 1Z3, Canada. mathers@interchange.ubc.ca
Wan
Xiang
X
Puil
Ernest
E
D000818:Animals; D000831:Animals, Newborn; D001463:Barbiturates / Q000494:pharmacology*; D001640:Bicuculline / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D004347:Drug Interactions; D018756:GABA Antagonists / Q000494:pharmacology; D006993:Hypnotics and Sedatives / Q000494:pharmacology*; D066298:In Vitro Techniques; D053444:Inhibitory Postsynaptic Potentials / Q000187:drug effects; D019579:Neocortex / Q000166:cytology* / Q000378:metabolism; D009474:Neurons / Q000187:drug effects*; D018408:Patch-Clamp Techniques / Q000379:methods; D010424:Pentobarbital; D010634:Phenobarbital; D051381:Rats; D017207:Rats, Sprague-Dawley; D011963:Receptors, GABA-A / Q000378:metabolism*; D013788:Thalamus / Q000166:cytology / Q000187:drug effects; D005680:gamma-Aminobutyric Acid / Q000494:pharmacology
D001463:Barbiturates; D018756:GABA Antagonists; D006993:Hypnotics and Sedatives; D011963:Receptors, GABA-A; D005680:gamma-Aminobutyric Acid; D010424:Pentobarbital; C032232:barbituric acid; D001640:Bicuculline; D010634:Phenobarbital