Delta oscillations induced by ketamine increase energy levels in sleep-wake related brain regions

Neuronal signaling consumes much of the brain energy, mainly through the restoration of the membrane potential (MP) by ATP-consuming ionic pumps. We have reported that, compared with waking, ATP levels increase during the initial hours of natural slow-wave sleep, a time with prominent electroencephalogram (EEG) delta oscillations (0.5-4.5 Hz). We have hypothesized that there is a delta oscillation-ATP increase coupling, since, during delta waves, neurons exhibit a prolonged hyperpolarizing phase followed by a very brief phase of action potentials. However, direct proof of this hypothesis is lacking, and rapid changes in EEG/neuronal activity preclude measurement in the naturally sleeping brain. Thus, to induce a uniform state with pure delta oscillations and one previously shown to be accompanied by a similar pattern of neuronal activity during delta waves as natural sleep, we used ketamine-xylazine treatment in rats. We here report that, with this treatment, the high-energy molecules ATP and ADP increased in frontal and cingulate cortices, basal forebrain, and hippocampus compared with spontaneous waking. Moreover, the degree of ATP increase positively and significantly correlated with the degree of EEG delta activity. Supporting the hypothesis of decreased ATP consumption during delta activity, the ATP-consuming Na+-K+-ATPase mRNA levels were significantly decreased, whereas the mRNAs for the ATP-producing cytochrome c oxidase (COX) subunits COX III and COX IVa were unchanged. Taken together, these data support the hypothesis of a cortical delta oscillation-dependent reduction in ATP consumption, thus providing the brain with increased ATP availability, and likely occurring because of reduced Na+-K+-ATPase-related energy consumption.