The role of ventral tegmental area dopamine neurons in emergence from dexmedetomidine, fentanyl, and ketamine anesthesia in rats.

Abstract

Dopamine neurons in the ventral tegmental area (VTA), a midbrain structure, have been widely implicated in promoting emergence from general anesthesia. However, most studies have focused on anesthetics that primarily target GABAA receptors. Whether these neurons also facilitate emergence from mechanistically diverse drug-induced unconscious states is not known. Here we examine the specific contribution of VTA dopamine neurons in restoring arousal following sevoflurane-, dexmedetomidine-, fentanyl-, and ketamine-induced unconsciousness. Adult Sprague Dawley rats received viral constructs driving selective expression in tyrosine hydroxylase-positive VTA neurons of either channelrhodopsin or the control protein, YFP. Accurate targeting in VTA TH:ChR was confirmed by assessing righting in response to photostimulation during continuous sevoflurane inhalation (1.4-2.0%). In a randomized block design, rats were exposed to dexmedetomidine (15 µg/kg IV bolus), fentanyl (50 µg/kg IV bolus), or ketamine (50 mg/kg IV infusion). Following loss of the righting reflex, behavioral arousal and frontal EEG activity were recorded with or without photostimulation. The proportion of animals righting during the light-on and light-off conditions was assessed in a mixed-effects Cox regression model, and spectral power differences were quantified with effect size estimates. Optogenetic stimulation of VTA dopamine neurons during continuous sevoflurane inhalation restored righting in VTA TH:ChR rats, with a median latency of 4.7 minutes (95%CI[2.6, 6.4]) following the onset of photostimulation. VTA TH:ChR rats were significantly more likely to right during photostimulation following dexmedetomidine (HR = 27.7, 95%CI[2.7, 287.1], p=0.0053), and responders showed attenuated spectral power in low frequencies (<12Hz) in VTA TH:ChR. Optogenetic stimulation did not affect behavioral nor neurophysiological measures of arousal following fentanyl. Finally, optogenetic stimulation in VTA TH:ChR rats modestly delayed emergence from ketamine sedation without altering EEG spectral power. These data suggest the role of dopamine VTA neurons in anesthetic emergence is agent-specific and likely shaped by distinct, and sometimes opposing, neural pathways.