The role of dopamine neurons in the ventral tegmental area in anesthetic-emergence and cognitive recovery
Anaesthesiology
Human Cognitive and Systems Neuroscience
Final Report Abstract
Anesthetics build the foundation of all major surgical interventions and are therefore indispensable in modern medicine. Nevertheless, their side effects can potentially be life-threatening. As there are no specific antagonists available for most agents, adverse effects are currently managed symptomatically. Moreover, emergence from anesthesia is primarily governed by the metabolic breakdown of the administered substance and cannot be actively accelerated. However, a prolonged emergence phase carries the risk of developing cardiopulmonary and neurocognitive complications. The ability to selectively reverse the effects of anesthetics could therefore significantly enhance patient safety. One promising target for facilitating emergence and restoring consciousness is the ventral tegmental area (VTA). The aim of the present project was to investigate the role of dopaminergic neurons in the VTA during emergence. To address this question, a rat model was used. Following viral injection into the VTA, the animals expressed light-sensitive receptors on their dopaminergic neurons that could be activated by optical stimulation. Various anesthetics were administered, and it was evaluated whether stimulation of dopaminergic neurons shortened the time to emergence. Activation of these neurons induced awakening during continuous sevoflurane inhalation and reduced the latency to emergence after dexmedetomidine injection. No significant effect was observed on emergence following fentanyl or ketamine administration. While the first part of the study focused on the return of basic reflexes, the second part used a touchscreen-based learning system to assess cognitive recovery. As a basis for evaluating the role of dopaminergic neurons in the VTA, emergence after administration of different anesthetics was analyzed. Following successful training, the animals received various anesthetics, and the times to recovery of consciousness and cognitive function were recorded. While cognitive performance recovered within one hour after sevoflurane or propofol, it remained impaired for up to three hours after ketamine, dexmedetomidine, or fentanyl administration. These findings revealed that the return of consciousness and the full recovery of cognitive abilities can occur independently. In an additional subproject, it was observed that repeated administration of fentanyl did not reduce the expression of life-threatening side effects such as respiratory depression. Overall, the findings open new perspectives for the development of clinically applicable strategies that enable targeted and safe restoration of consciousness, thereby sustainably improving patient safety and postoperative recovery.
Publications
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"A Rat Model of Repeated, High-dose Fentanyl Abuse Reveals Minimal Tolerance to Unconsciousness, Muscle Rigidity and Respiratory Depression.” in Association of University Anesthesiologists 2024 Annual Meeting (2024). St. Louis, MI, USA
D. P. Obert, G. H. Park, D. R. Schreier, C. Troyas, K. F. Vincent KF & K. Solt
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"A Rat Model of Repeated, High-dose Fentanyl Abuse Reveals Minimal Tolerance to Unconsciousness, Muscle Rigidity and Respiratory Depression.” in National Institute of Drug Abuse International Forum (2024). Montreal, Canada
D. P. Obert, G. H. Park, D. R. Schreier, C. Troyas, K. F. Vincent KF & K. Solt
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"A Rat Model of Repeated, High-dose Fentanyl Abuse Reveals Minimal Tolerance to Unconsciousness, Muscle Rigidity and Respiratory Depression.” in The International College of Neuropsychopharmacology Congress (2024). Tokyo, Japan
D. P. Obert, G. H. Park, D. R. Schreier, C. Troyas, K. F. Vincent KF & K. Solt
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"The Touchscreen-based Paired Associates Learning Task: A Novel Method to Assess Recovery of Long-term Memory in Rats Recovering from General Anesthesia.” in International Anesthesia Research Society 2024 Annual Meeting (2024). Seattle, WA, USA
D. P. Obert, G. H. Park, K. F. Vincent & K. Solt
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Electrical stimulation of the ventral tegmental area restores consciousness from sevoflurane-, dexmedetomidine-, and fentanyl-induced unconsciousness in rats. Brain Stimulation, 17(3), 687-697.
Vincent, Kathleen F.; Zhang, Edlyn R.; Cho, Angel J.; Kato-Miyabe, Risako; Mallari, Olivia G.; Moody, Olivia A.; Obert, David P.; Park, Gwi H. & Solt, Ken
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Repeated High-dose Fentanyl Administration in Rats Reveals Minimal Tolerance to Unconsciousness, Bradycardia, Muscle Rigidity, and Respiratory Depression. Anesthesiology, 142(3), 465-475.
Obert, David P.; Park, Gwi H.; Strong, Kaitlyn; Schreier, David R.; Korn, Elizabeth; Troyas, Carla; Vincent, Kathleen F. & Solt, Ken
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The iPAL: A Touchscreen-based Method to Assess Recovery of Long-term Memory of Rats after Anesthesia.” in Best Abstracts in ANESTHESIOLOGY® 2024 annual meeting (2024). Philadelphia, PA, USA
D. P. Obert, G. H. Park, K. F. Vincent & K. Solt
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“Identification of drug specific arousal circuits in the midbrain for anesthetic reversal.” in Society for Neuroscience in Anesthesiology and Critical Care Annual Meeting (2024). Denver, CO, USA
D. P. Obert
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Drug-specific recovery of long-term memory and visual discrimination after anaesthetic-induced unconsciousness in rats. British Journal of Anaesthesia, 135(4), 953-964.
Obert, David P.; Park, Gwi H.; Vincent, Kathleen F. & Solt, Ken
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“Leveraging dopaminergic circuits to reverse diverse anesthetics” in Gordon Research Conference on Consciousness, Anesthesia and Evolutionary Biology (2025). Lucca, Italy
D. P. Obert, K. F. Vincent, E. Coulter, G. H. Park & K. Solt
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“Leveraging dopaminergic circuits to reverse diverse anesthetics” in Oral Presentations in Gordon Research Seminar on Consciousness, Anesthesia and Evolutionary Biology (2025). Lucca, Italy
D. P. Obert, K. F. Vincent, E. Coulter, G. H. Park & K. Solt
