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Background: Orexin can facilitate emergence after general anaesthesia via multiple neural pathways. Dopaminergic neurones in the ventral tegmental area (VTA) participate in behavioural arousal from anaesthesia. We investigated the regulation of dopaminergic VTA neurones by orexinergic neurones during emergence from general anaesthesia. Methods: Orexins were microinjected into the VTA to determine the effects on isoflurane anaesthesia induction, emergence, and maintenance. Orexin receptors and dopaminergic neurones in the VTA were identified using immunofluorescence. Orexinergic terminals in the VTA were optogenetically regulated to detect the endogenous orexinmediated regulation of dopaminergic neurones during anaesthesia in Hcrt cre rats. Results: Injection of orexin-A (100 pmol) into the VTA reduced emergence time [from 949 (118) to 727 (101) s; P¼0.0058] and reduced the electroencephalographic burstesuppression ratio (BSR) (26.6 [10.2]% vs 44.3 [6.8]%; P¼0.0027) during isoflurane anaesthesia. The percentage of dopaminergic neurones that expressed either orexin-1 receptor or orexin-2 receptor was 73.4 (5.0)% and 74.4 (62.4)%, respectively. Optogenetic activation of orexinergic projections to the VTA reduced the BSR (from 40.5 [2.7]% to 22.4 [11.8]%; P¼0.0019) and facilitated emergence (915 [89] vs 685 [68] s; P¼0.0026), whereas optical inhibition prolonged the time to wakefulness (from 941 [92] to 1279 [250] s; P¼0.011). Dopaminergic neurones in the VTA showed increased firing frequency (387 [78]% of control, P¼0.005) after bath application of orexin-A. Conclusions: Orexin promotes emergence from isoflurane anaesthesia through activation of dopaminergic neurones in the VTA.

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