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Biol Psychiatry. 2018 Oct 15;84(8):611-623. doi: 10.1016/j.biopsych.2018.04.018. Epub 2018 May 8.

The Lateral Habenula Directs Coping Styles Under Conditions of Stress via Recruitment of the Endocannabinoid System.

Author information

1
Department of Psychology, Washington State University, Pullman, Washington.
2
Department of Integrative Physiology and Neuroscience, Washington State University, Pullman, Washington.
3
Department of Cell Biology and Anatomy, Hotchkiss Brain Institute, University of Calgary, Calgary, Alberta, Canada; Department of Psychiatry, Hotchkiss Brain Institute, University of Calgary, Calgary, Alberta, Canada.
4
Department of Neurosciences, University of the Basque Country, Universidad del País Vasco/Euskal Herriko Unibertsitatea, Leioa, Spain; Achucarro Basque Center for Neuroscience, Science Park of the Universidad del País Vasco/Euskal Herriko Unibertsitatea, Leioa, Spain.
5
Department of Neuroscience, The Scripps Research Institute, La Jolla, California.
6
Department of Neurosciences, University of the Basque Country, Universidad del País Vasco/Euskal Herriko Unibertsitatea, Leioa, Spain; Achucarro Basque Center for Neuroscience, Science Park of the Universidad del País Vasco/Euskal Herriko Unibertsitatea, Leioa, Spain; Division of Medical Sciences, University of Victoria, Victoria, British Columbia, Canada.
7
Department of Pharmacology and Toxicology and Neuroscience Research Center, Medical College of Wisconsin, Milwaukee, Wisconsin.
8
Department of Psychology, Washington State University, Pullman, Washington; Department of Integrative Physiology and Neuroscience, Washington State University, Pullman, Washington. Electronic address: ryan.mclaughlin@wsu.edu.

Abstract

BACKGROUND:

The ability to effectively cope with stress is a critical determinant of disease susceptibility. The lateral habenula (LHb) and the endocannabinoid (ECB) system have independently been shown to be involved in the selection of stress coping strategies, yet the role of ECB signaling in the LHb remains unknown.

METHODS:

Using a battery of complementary techniques in rats, we examined the localization of type-1 cannabinoid receptors (CB1Rs) and assessed the behavioral and neuroendocrine effects of intra-LHb CB1R manipulations. We further tested the extent to which the ECB system in the LHb is impacted following chronic unpredictable stress or social defeat stress, and whether manipulation of LHb CB1Rs can bias coping strategies in rats with a history of chronic stress.

RESULTS:

Electron microscopy studies revealed CB1R expression on presynaptic axon terminals, postsynaptic membranes, mitochondria, and glial processes in the rat LHb. In vivo microdialysis experiments indicated that acute stress increased the amount of 2-arachidonoylglycerol in the LHb, while intra-LHb CB1R blockade increased basal corticosterone, augmented proactive coping strategies, and reduced anxiety-like behavior. Basal LHb 2-arachidonoylglycerol content was similarly elevated in rats that were subjected to chronic unpredictable stress or social defeat stress and positively correlated with adrenal weight. Finally, intra-LHb CB1R blockade increased proactive behaviors in response to a novel conspecific, increasing approach behaviors irrespective of stress history and decreasing the latency to be attacked during an agonistic encounter.

CONCLUSIONS:

Alterations in LHb ECB signaling may be relevant for development of stress-related pathologies in which LHb dysfunction and stress-coping impairments are hallmark symptoms.

KEYWORDS:

Anxiety; CB(1) receptor; Endocannabinoid; Lateral habenula; Rat; Stress coping

PMID:
29887035
PMCID:
PMC6162143
DOI:
10.1016/j.biopsych.2018.04.018
[Indexed for MEDLINE]
Free PMC Article

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