The septal-hippocampal cholinergic pathway: Role in antagonism of pentobarbital anesthesia and regulation by various afferents

Earlier studies have demonstrated that pentobarbital reduces the turnover rate of acetylcholine (ACh) in hippocampus and that this effect may be mediated via the septal-hippocampal cholinergic pathway. Moreover, the narcosis associated with the administration of pentobarbital may be reversed by intraseptal injection of such chemically diverse compounds as bicuculline, a potent γ-aminobutyric acid antagonist; thyrotropin-releasing hormone, a neuroactive tripeptide; and kainic acid, a rigid analog of glutamate. To determine whether or not these three compounds modulate the metabolism of ACh in hippocampus, they have been injected intraseptally in pentobarbital-pretreated rats and the turnover rate of ACh has been determined by gas chromatography-mass fragmentography. Pentobarbital produces a dose-dependent decrease in the turnover rate of ACh in cortex and hippocampus but not in striatum. The effect appears to be maximum at 30 min and returns to normal within 15 min of recovering the righting reflex. Slow local infusion of either bicuculline or thyrotropin-releasing hormone into the septum reverses the pentobarbital-induced narcosis and antagonizes the pentobarbital-induced decrease in the hippocampal turnover rate of ACh. Administration of kainic acid into the lateral, but not the medial, septum reduces specifically the glutamic acid decarboxylase activity in the ipsilateral septum without altering the choline acetyltransferase activity or the turnover rate of ACh in the hippocampus. Moreover, kainic acid injected into the lateral septum antagonizes the pentobarbital narcosis and reverses the pentobarbital-induced decrease in the ACh turnover rate in the ipsilateral hippocampus, but not in the contralateral hippocampus. It appears that all three compounds antagonize the pentobarbital-induced decrease in hippocampal ACh turnover rate and the pentobarbital narcosis by modulating neurons in the lateral septum, presumably through an action on the GABAergic interneurons.