LAUSR

Background: Dexmedetomidine induces a sedative response that is associated with rapid arousal. To elucidate the underlying mechanisms, the authors hypothesized that dexmedetomidine increases the activity of dopaminergic neurons in the ventral tegmental area, and that this action contributes to the unique sedative properties of dexmedetomidine. Methods: Only male mice were used. The activity of ventral tegmental area dopamine neurons was measured by a genetically encoded Ca2+ indicator and patch-clamp recording. Dopamine neurotransmitter dynamics in the medial prefrontal cortex and nucleus accumbens were measured by a genetically encoded dopamine sensor. Ventral tegmental area dopamine neurons were inhibited or activated by a chemogenetic approach, and the depth of sedation was estimated by electroencephalography. Results: Ca2+ signals in dopamine neurons in the ventral tegmental area increased after intraperitoneal injection of dexmedetomidine (40 μg/kg; dexmedetomidine, 16.917 [14.882; 21.748], median [25%; 75%], vs. saline, –0.745 [–1.547; 0.359], normalized data, P = 0.001; n = 6 mice). Dopamine transmission increased in the medial prefrontal cortex after intraperitoneal injection of dexmedetomidine (40 μg/kg; dexmedetomidine, 10.812 [9.713; 15.104], median [25%; 75%], vs. saline, –0.498 [–0.664; –0.355], normalized data, P = 0.001; n = 6 mice) and in the nucleus accumbens (dexmedetomidine, 8.543 [7.135; 11.828], median [25%; 75%], vs. saline, –0.329 [–1.220; –0.047], normalized data, P = 0.001; n = 6 mice). Chemogenetic inhibition or activation of ventral tegmental area dopamine neurons increased or decreased slow waves, respectively, after intraperitoneal injection of dexmedetomidine (40 μg/kg; delta wave: two-way repeated measures ANOVA, F[2, 33] = 8.016, P = 0.002; n = 12 mice; theta wave: two-way repeated measures ANOVA, F[2, 33] = 22.800, P < 0.0001; n = 12 mice). Conclusions: Dexmedetomidine activates dopamine neurons in the ventral tegmental area and increases dopamine concentrations in the related forebrain projection areas. This mechanism may explain rapid arousability upon dexmedetomidine sedation. Dexmedetomidine, via α2 receptor–dependent mechanisms, induces activation of dopaminergic neurons in the ventral tegmental area of adult mice. Chemogenetic approaches together with electroencephalographic recordings reveal that the activation of dopaminergic neurons in the ventral tegmental area may contribute to rapid arousability during dexmedetomidine sedation. Supplemental Digital Content is available in the text.