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Promoting arousal by manipulating certain brain regions and/or neurotransmitters has been a recent research focus, with the goal of trying to improve recovery from general anesthesia. The current study tested the hypothesis that a single subanesthetic dose of ketamine during isoflurane anesthesia would increase cholinergic tone in the prefrontal cortex and accelerate recovery.Adult male rats were implanted with electroencephalography electrodes (frontal, parietal, and occipital cortex) and a microdialysis guide cannula targeted for the prefrontal cortex. After establishing general anesthesia with isoflurane, animals were randomly assigned to receive a saline control or ketamine injection. When isoflurane was discontinued nearly 90 min after drug or saline administration, recovery from anesthesia was measured by experimenters and blinded observers. During the entire experiment, electrophysiologic signals were recorded and acetylcholine was quantified by high-performance liquid chromatography with electrochemical detection.A single dose of subanesthetic ketamine caused an initial 125% increase in burst suppression ratio (last isoflurane sample: 37.48 ± 24.11% vs. isoflurane after ketamine injection: 84.36 ± 8.95%; P < 0.0001), but also a significant 44% reduction in emergence time (saline: 877 ± 335 s vs. ketamine: 494 ± 108 s; P = 0.0005; n = 10 per treatment). Furthermore, ketamine caused a significant 317% increase in cortical acetylcholine release (mean after ketamine injection: 0.18 ± 0.16 pmol vs. ketamine recovery: 0.75 ± 0.41 pmol; P = 0.0002) after isoflurane anesthesia was discontinued.Administration of subanesthetic doses of ketamine during isoflurane anesthesia increases anesthetic depth but—paradoxically—accelerates the recovery of consciousness, possibly through cholinergic mechanisms.