Abstract

The present study was designed to determine whether HC-3, a potent inhibitor of choline uptake and therefore of acetylcholine (ACh) synthesis, could provide additional evidence that cholinergic neurons are involved in the neocortical and limbic EEG activating systems. The effects of HC-3 were determined on the EEG and brain ACh content of locally anesthetized, decamethonium-immobilized, artificially respired dogs. Intravenous HC-3 (5 and 10 mg/kg) did not produce consistent EEG effects. To circumvent the blood-brain barrier, HC-3 was administered intraventricularly into the left lateral cerebral ventricle in total doses of 1.0 µg to 5.0 mg. No obvious change in EEG activity occurred after the 1.0-µg dose. After 10 µg, high voltage, spike-like slow waves appeared in the amygdala without the occurrence of concomitant EEG changes in the neocortex. The initial effects produced by 50 µg to 1.25 mg were characterized by high voltage hippocampal fast waves in addition to amygdaloid slow waves. EEG seizures frequently occurred after 2.5 and 5.0 mg. Two to 4 hr after 50 µg to 5.0 mg, high voltage neocortical slow waves appeared. Once slow waves were present, high frequency electrical and peripheral nociceptive stimulation of the mesencephalic reticular formation and posterior hypothalamus no longet elicited an activation response. Although EEG activation elicited by high frequency stimulation of the diffuse thalamic projection system was also prevented, recruiting responses recorded in the neocortex and caudate nucleus by low frequency stimulation of the same thalamic areas were only slightly modified. Choline (5-50 mg/kg i.v.) produced a delayed and transient reversal of the HC-3 effects. A significant decrease (41-79% in the ACh content of the amygdala, hippocampus, medial thalamus, reticular formation and caudate nucleus occurred 4 hr after 50 µg and 5.0 mg of HC-3 intraventricularly. Neocortical ACh levels were not altered significantly. Similar effects did not occur 1 hr after 50 µg of HC-3 intraventricularly or 4 hr after 5.0 and 10 mg/kg of HC-3 i.v. It is concluded that the effect of HC-3 on EEG activation is associated with reduction of cerebral ACh. However, an action of HC-3 on other choline-containing substances in the brain was not ruled out as a possible mechanism of action.