Resistance to state transitions in responsiveness is differentially modulated by different volatile anaesthetics in male mice.

ABSTRACT

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 Rst. 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 Rst is distinct from drug potency and is differentially modulated by different anaesthetics. METHODS: Adult (14-24 weeks old) C57BL/6J male mice (n=60) 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 Rst was differentially modulated by different anaesthetics (F[2, 56.01]=49.59; 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]=16.72; 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.