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Lesioning of the ventrolateral preoptic nucleus alters isoflurane-induced hypnosis in a time-dependent fashion

Moore JT, Mccarren HS, Beck SG, Kelz MB (2010) Lesioning of the ventrolateral preoptic nucleus alters isoflurane-induced hypnosis in a time-dependent fashion. Neuroscience 2010 Abstracts 300.28/KKK36. Society for Neuroscience, San Diego, CA.

Summary: Despite 160 years of clinical use, the neural mechanisms through which general anesthetics act remain unknown. One possibility is that anesthetics exert their hypnotic effects by acting on the endogenous arousal neural circuitry, including the wake-promoting orexinergic neurons of the hypothalamus and the sleep-promoting GABAergic and galaninergic neurons of the ventrolateral preoptic nucleus (VLPO). We have previously demonstrated that orexinergic neurons play an essential role during emergence from general anesthesia but not during anesthetic induction (Kelz et al., 2008). Here, we present evidence that the VLPO exerted a modulatory role in the induction of anesthetic hypnosis. We used c-Fos immunohistochemistry to analyze the activity of VLPO neurons in brain slices of mice sacrificed after two hours of anesthetic exposure. Whereas anesthetic exposure produced a decrease in the number of c-Fos-positive nuclei in most brain areas, this was not true for the VLPO: exposure to the volatile anesthetics isoflurane or halothane produced a rapid, dose-dependent increase in the number of c-Fos-positive nuclei in the VLPO, implying that hypnotic doses of volatile anesthetics increased the firing rates of VLPO neurons. To determine whether activation of the VLPO was necessary for anesthetic-induced hypnosis, galanin-saporin was used to produce targeted lesions of VLPO neurons. Six days following surgery, the bilaterally lesioned mice were more resistant to induction with isoflurane than control animals in a loss of righting reflex assay. However, 24 days following surgery the lesioned animals were more sensitive to isoflurane than controls. This time-dependent effect was likely due to the build-up of sleep debt–which is known to reduce the anesthetic dose needed to induce hypnosis–as a result of the insomnia-producing VLPO lesions (Lu et al., 2000). These findings are consistent with the VLPO playing a key role in the induction of volatile anesthetic-induced hypnosis, though formal proof will require acute manipulations of VLPO activity that do not produce a sleep debt confound.

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