ACTIVATING DOPAMINE NEURONS IN THE VENTRAL TEGMENTAL AREA FACILITATES COGNITIVE RECOVERY FOLLOWING DEXMEDETOMIDINE- INDUCED LOSS OF CONSCIOUSNESS IN RATS

Abstract Background As the number of people requiring general anesthesia continues to increase (Meara et al., 2015), understanding how consciousness and cognition are restored following drug-induced loss of consciousness becomes increasingly important. Rodent studies indicate that dopaminergic neurons in the ventral tegmental area (VTA) are critically involved in restoring arousal following general anesthesia (Vincent and Solt, 2023). Whether these circuits contribute to cognitive recovery, however, is unknown. Recently, a novel cognitive recovery testing paradigm for rodents was established using an adapted version of the 5-Choice Serial Reaction Time Task (5CSRTT) (Vincent et al., 2021). In it, higher order neurocognitive processes are tracked in real-time following anesthesia to establish cognitive recovery trajectories. Dexmedetomidine (an alpha 2A adrenergic receptor agonist) and ketamine (an NMDA receptor antagonist) are commonly used clinical anesthetics with distinct molecular mechanisms. It was recently reported that cognitive deficits are prolonged following dexmedetomidine- and ketamine- induced loss of consciousness in rats. Identifying mechanisms to facilitate cognitive recovery following the administration of these commonly used anesthetics would be of great clinical importance. Aims & Objectives The aim of this study was to assess the contribution of VTA dopaminergic neurons in cognitive recovery following dexmedetomidine- and ketamine-induced loss of consciousness using a rodent model of post-anesthetic cognitive recovery. Methods Excitatory Designer Receptors Exclusively Activated by Designer Drugs (DREADDs) were expressed in VTA dopamine neurons in Sprague Dawley rats (N=8) trained on the 5CSRTT using two viral constructs: AAV9-rTH-Cre and AAV2-DIO-hM3D(Gq). After allowing three weeks for receptor expression, dexmedetomidine (20 μ g/kg, i.v.) or ketamine (50 mg/kg, i.v.) was administered at doses sufficient to induce loss of righting, a proxy for loss of consciousness in rodents. Rats were then administered either clozapine-N-oxide (CNO) to activate VTA dopaminergic neurons, or saline in a randomized order. Rats were placed supine in the testing chamber to recover consciousness, measured by the return of the righting reflex. After righting, rats were tested for three hours on the 5CSRTT to assess latency to recover working memory and sustained attention. The probability of recovering memory and attention was compared between CNO and saline treatment using a mixed effects Cox regression. Results Following righting, CNO treatment significantly accelerated recovery of accuracy performance (p=.0330) after dexmedetomidine, but not after ketamine. CNO also significantly accelerated recovery of a low omission performance (p=.0019) following dexmedetomidine but had no impact following ketamine. Discussion & Conclusions Selective activation of VTA dopaminergic neurons hastens neurocognitive recovery following dexmedetomidine-induced loss of consciousness in rats. However, this circuit has no impact on cognitive function following ketamine. These data suggest there are distinct mechanisms by which the brain restores cognitive function following drug-induced breaks in consciousness. Identifying these mechanisms will be key to designing effective strategies for facilitating cognitive recovery following general anesthesia. References MEARA, J. G., LEATHER, A. J., HAGANDER, L., ALKIRE, B. C., ALONSO, N., AMEH, E. A., BICKLER, S. W., CONTEH, L., DARE, A. J., DAVIES, J., MERISIER, E. D., EL-HALABI, S., FARMER, P. E., GAWANDE, A., GILLIES, R., GREENBERG, S. L., GRIMES, C. E., GRUEN, R. L., ISMAIL, E. A., KAMARA, T. B., LAVY, C., LUNDEG, G., MKANDAWIRE, N. C., RAYKAR, N. P., RIESEL, J. N., RODAS, E., ROSE, J., ROY, N., SHRIME, M. G., SULLIVAN, R., VERGUET, S., WATTERS, D., WEISER, T. G., WILSON, I. H., YAMEY, G. &YIP, W. 2015. Global Surgery 2030: evidence and solutions for achieving health, welfare, and economic development. Lancet, 386, 569-624. VINCENT, K. F. &SOLT, K. 2023. Modulating anesthetic emergence with pathway-selective dopamine signaling. Curr Opin Anaesthesiol. VINCENT, K. F., ZHANG, E. R., KATO, R., CHO, A., MOODY, O. A. &SOLT, K. 2021. Return of the righting reflex does not portend recovery of cognitive function in anesthetized rats. Frontiers in Systems Neuroscience, 15.