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Featured ArticleResearch Articles, Systems/Circuits

Nociceptive Stimuli Activate the Hypothalamus–Habenula Circuit to Inhibit the Mesolimbic Reward System and Cocaine-Seeking Behaviors

Soo Min Lee, Han Byeol Jang, Yu Fan, Bong Hyo Lee, Sang Chan Kim, Kyle B. Bills, Scott C. Steffensen and Hee Young Kim
Journal of Neuroscience 7 December 2022, 42 (49) 9180-9192; DOI: https://doi.org/10.1523/JNEUROSCI.0577-22.2022
Soo Min Lee
1Emotion, Cognition & Behavior Research Group, Korea Brain Research Institute, Daegu 41062, South Korea
3Department of Physiology, College of Korean Medicine, Daegu Haany University, Daegu 42158, South Korea
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Han Byeol Jang
3Department of Physiology, College of Korean Medicine, Daegu Haany University, Daegu 42158, South Korea
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Yu Fan
2Department of Human Anatomy and Histoembryology, Nanjing University of Chinese Medicine, Nanjing 210023, China
3Department of Physiology, College of Korean Medicine, Daegu Haany University, Daegu 42158, South Korea
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Bong Hyo Lee
3Department of Physiology, College of Korean Medicine, Daegu Haany University, Daegu 42158, South Korea
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Sang Chan Kim
4Medical Research Center, College of Korean Medicine, Daegu Haany University, Gyeongsan 38610, South Korea
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Kyle B. Bills
5Department of Biomedical Sciences, Noorda College of Osteopathic Medicine, Provo, Utah 84606
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Scott C. Steffensen
6Department of Psychology and Neuroscience, Brigham Young University, Provo, Utah 84602
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Hee Young Kim
7Department of Physiology, Yonsei University College of Medicine, Seoul 03722, South Korea
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Abstract

Nociceptive signals interact with various regions of the brain, including those involved in physical sensation, reward, cognition, and emotion. Emerging evidence points to a role of nociception in the modulation of the mesolimbic reward system. The mechanism by which nociception affects dopamine (DA) signaling and reward is unclear. The lateral hypothalamus (LH) and the lateral habenula (LHb) receive somatosensory inputs and are structurally connected with the mesolimbic DA system. Here, we show that the LH–LHb pathway is necessary for nociceptive modulation of this system using male Sprague Dawley rats. Our extracellular single-unit recordings and head-mounted microendoscopic calcium imaging revealed that nociceptive stimulation by tail pinch excited LHb and LH neurons, which was inhibited by chemical lesion of the LH. Tail pinch increased activity of GABA neurons in ventral tegmental area, decreased the extracellular DA level in the nucleus accumbens ventrolateral shell in intact rats, and reduced cocaine-increased DA concentration, which was blocked by disruption of the LH. Furthermore, tail pinch attenuated cocaine-induced locomotor activity, 22 and 50 kHz ultrasonic vocalizations, and reinstatement of cocaine-seeking behavior, which was inhibited by chemogenetic silencing of the LH–LHb pathway. Our findings suggest that nociceptive stimulation recruits the LH–LHb pathway to inhibit mesolimbic DA system and drug reinstatement.

SIGNIFICANCE STATEMENT The LHb and the LH have been implicated in processing nociceptive signals and modulating DA release in the mesolimbic DA system. Here, we show that the LH–LHb pathway is critical for nociception-induced modulation of mesolimbic DA release and cocaine reinstatement. Nociceptive stimulation alleviates extracellular DA release in the mesolimbic DA system, cocaine-induced psychomotor activities, and reinstatement of cocaine-seeking behaviors through the LH–LHb pathway. These findings provide novel evidence for sensory modulation of the mesolimbic DA system and drug addiction.

  • cocaine addiction
  • dopamine
  • lateral habenula
  • lateral hypothalamus
  • nociception

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The Journal of Neuroscience: 42 (49)
Journal of Neuroscience
Vol. 42, Issue 49
7 Dec 2022
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Nociceptive Stimuli Activate the Hypothalamus–Habenula Circuit to Inhibit the Mesolimbic Reward System and Cocaine-Seeking Behaviors
Soo Min Lee, Han Byeol Jang, Yu Fan, Bong Hyo Lee, Sang Chan Kim, Kyle B. Bills, Scott C. Steffensen, Hee Young Kim
Journal of Neuroscience 7 December 2022, 42 (49) 9180-9192; DOI: 10.1523/JNEUROSCI.0577-22.2022

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Nociceptive Stimuli Activate the Hypothalamus–Habenula Circuit to Inhibit the Mesolimbic Reward System and Cocaine-Seeking Behaviors
Soo Min Lee, Han Byeol Jang, Yu Fan, Bong Hyo Lee, Sang Chan Kim, Kyle B. Bills, Scott C. Steffensen, Hee Young Kim
Journal of Neuroscience 7 December 2022, 42 (49) 9180-9192; DOI: 10.1523/JNEUROSCI.0577-22.2022
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Keywords

  • cocaine addiction
  • dopamine
  • lateral habenula
  • lateral hypothalamus
  • nociception

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