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

Background: 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 GABA A 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. Methods: 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. Results: 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. Conclusions: 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.