Neural mechanisms of ketamine-induced anesthesia.

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The sites of action of ketamine (CI-581; 2-(0-chlorophenyl)-2-methylamino cyclohexamine HCl) were determined in the central nervous system using electrophysiological techniques in both acute and chronic cat experiments. It was demonstrated in chronic preparations that the cataleptic anesthetic state induced by ketamine is accompanied by an alternating pattern of hypersynchronous delta wave bursts and low voltage, fast wave activity in the neocortex and thalamus. The delta wave bursts had a distribution in the neocortex similar to that of spindles produced by low doses of barbiturates or natural sleep. Subcortically, the delta wave bursts were observed prominently in the thalamus and in the caudate nucleus. The EEG patterns of the diffusely projecting thalamic nuclei were closely related phasically to the delta waves of the neocortex. EEG changes in the midbrain reticular formation and hypothalamus were not as prominent. Paradoxically, the hippocampus showed theta “arousal” waves during thedelta wave burst period of the thalamo-neocortical system. This functional dissociation between the thalamo-neocortical and limbic system was one of the EEG characteristics of ketamine. Ketamine, in contrast to the barbiturates, depressed the recruiting response at a time when neocortical EEG activation was minimally affected. Somatosensory potentials evoked from stimulation of the median nerve were depressed primarily in the nonspecific thalamic nuclei, midbrain reticular formation, somatosensory cortex and sensory relay nuclei, respectively, with minimal anesthetic doses. Multiple neuronal unit activity showed clear grouping in the thalamus. The closest relationship of multiple unit activity to the delta waves in the neocortex was observed in the diffusely projecting thalamic nuclei. After ketamine the reticular formation showed neither grouping nor suppression of multiple unit activity during the neocortical delta bursts. Based upon these observations, the site of action of ketamine in minimal anesthetic doses appears to be in the non-specific thalamo-neocortical system. This system seems to be a primary factor in producing the hypersynchronous delta wave burst pattern in the EEG.