Newly Published
Perioperative Medicine  |   May 2020
Dexmedetomidine Activation of Dopamine Neurons in the Ventral Tegmental Area Attenuates the Depth of Sedation in Mice
Author Notes
  • From the Department of Anesthesiology, First Affiliated Hospital of Anhui Medical University, Hefei, China (G.Q., Y.W., Y.L.); School of Life Science and Technology, ShanghaiTech University, Shanghai, China (X.Z., J.H.); Department of Anesthesiology and Perioperative Medicine, Xijing Hospital, The Fourth Military Medical University, Xi’an, Shanxi, China (L.L., H.D.); Chinese Institute for Brain Research, Beijing, China (W.S.); Department of Anesthesiology, International Peace Maternity and Child Health Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China (Z.Y.); Department of Anesthesiology, Anhui No. 2 Provincial People’s Hospital, Hefei, Anhui, China (Y.W.); and Coinnovation Center of Neuroregeneration, Nantong University, Nantong, China (J.H.).
  • Supplemental Digital Content is available for this article. Direct URL citations appear in the printed text and are available in both the HTML and PDF versions of this article. Links to the digital files are provided in the HTML text of this article on the Journal’s Web site (www.anesthesiology.org).
    Supplemental Digital Content is available for this article. Direct URL citations appear in the printed text and are available in both the HTML and PDF versions of this article. Links to the digital files are provided in the HTML text of this article on the Journal’s Web site (www.anesthesiology.org).×
  • G.Q. and Y.W. contributed equally to this article.
    G.Q. and Y.W. contributed equally to this article.×
  • Submitted for publication October 3, 2019. Accepted for publication April 9, 2020.
    Submitted for publication October 3, 2019. Accepted for publication April 9, 2020.×
  • Correspondence: Address correspondence to Dr. Hu: School of Life Science and Technology, ShanghaiTech University, Shanghai 201210, China. huji@shanghaitech.edu.cn. Information on purchasing reprints may be found at www.anesthesiology.org or on the masthead page at the beginning of this issue. Anesthesiology’s articles are made freely accessible to all readers, for personal use only, 6 months from the cover date of the issue.
Article Information
Perioperative Medicine
Perioperative Medicine   |   May 2020
Dexmedetomidine Activation of Dopamine Neurons in the Ventral Tegmental Area Attenuates the Depth of Sedation in Mice
Anesthesiology Newly Published on May 12, 2020. doi:https://doi.org/10.1097/ALN.0000000000003347
Anesthesiology Newly Published on May 12, 2020. doi:https://doi.org/10.1097/ALN.0000000000003347
Abstract

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.

Editor’s Perspective:

What We Already Know about This Topic:

  • Dexmedetomidine is a highly selective α2 receptor agonist with unique sedative properties

  • Dopaminergic neurons in the ventral tegmental area express α2 receptors, and activation of these cells induces recovery from anesthesia

  • The effects of dexmedetomidine on dopaminergic neurons of the ventral tegmental area are incompletely understood

What This Article Tells Us That Is New:

  • 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