A high-cholesterol diet leads to faster induction of general anesthesia in two model animals: D. magna and C. elegans

General anesthesia (GA) has been under scientific scrutiny since its discovery more than a century ago, resulting in conceptually different proposed mechanisms to explain its origin and operation. Two mechanisms stand out: the lipid and the protein hypothesis. The Meyer-Overton rule (the more anesthetics dissolve in octanol, the greater their action) backups the first hypothesis, while the ligand-receptor interaction, specifically on ion channels, sustains the second. A recent study on Drosophila melanogaster draws attention to the possibility that both paradigms come together to explain GA synergistically, with the important caveat that this hybrid mechanism lies in the existence of lipid rafts in which cholesterol plays an essential role. Using two model organisms, the water flea (D. magna) and the nematode C. elegans, we give a further step to clarify this puzzle by carrying out anesthetic experiments with xenon and nitrous oxide. First, the obtained dose-response curves are very steep, implying that Hill coefficients greater than one are needed to describe them correctly, supporting an unspecific action mechanism. Second, we show that the animals’ response to both gases is influenced by a cholesterol diet modification, thus proving that this lipid promotes anesthetic induction. Our findings reenforce the idea that GA is driven by an allosteric induction rather than selective actions on single-target receptors.