Background: Recent studies point to a fundamental distinction between population-based and individual-based anaesthetic pharmacology. At the population level, anaesthetic potency is defined as the relationship between drug concentration and the likelihood of response to a stimulus. At the individual level, even when the anaesthetic concentration is held constant, fluctuations between the responsive and unresponsive states are observed. Notably, these spontaneous fluctuations exhibit resistance to state transitions R st . Therefore, the response probability in each individual depends not just upon the drug concentration, but also upon responses to previous stimuli. Here, we hypothesise that R st is distinct from drug potency and is differentially modulated by different anaesthetics. Methods: Adult (14e24 weeks old) C57BL/6J male mice (n¼60) were subjected to repeated righting reflex (RR) assays at equipotent steady-state concentrations of isoflurane (0.6 vol%), sevoflurane (1.0 vol%), and halothane (0.4 vol%). Results: Fluctuations in RR were observed for all tested anaesthetics. Analysis of these fluctuations revealed that R st was differentially modulated by different anaesthetics (F[2, 56.01]¼49.59; P<0.0001). Fluctuations in RR were modelled using a stochastic dynamical system. This analysis confirmed that the amount of noise that drives behavioural state transitions depends on the anaesthetic agent (F[2, 42.86]¼16.72; P<0.0001). Conclusions: Whilst equipotent doses of distinct anaesthetics produce comparable population response probabilities, they engage dramatically different dynamics in each individual animal. This manifests as a differential aggregate propensity to exhibit state transitions. Thus, resistance to state transitions is a fundamentally distinct, novel measure of individualised anaesthetic pharmacology.
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