The Lateral Habenula Directs Coping Styles Under Conditions of Stress via Recruitment of the Endocannabinoid System. Biol Psychiatry 2018 Oct 15;84(8):611-623
Date
06/12/2018Pubmed ID
29887035Pubmed Central ID
PMC6162143DOI
10.1016/j.biopsych.2018.04.018Scopus ID
2-s2.0-85048097931 (requires institutional sign-in at Scopus site) 35 CitationsAbstract
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.
Author List
Berger AL, Henricks AM, Lugo JM, Wright HR, Warrick CR, Sticht MA, Morena M, Bonilla I, Laredo SA, Craft RM, Parsons LH, Grandes PR, Hillard CJ, Hill MN, McLaughlin RJAuthor
Cecilia J. Hillard PhD Associate Dean, Center Director, Professor in the Pharmacology and Toxicology department at Medical College of WisconsinMESH terms used to index this publication - Major topics in bold
Adaptation, PsychologicalAnimals
Arachidonic Acids
Cannabinoid Receptor Agonists
Corticosterone
Depression
Disease Models, Animal
Endocannabinoids
Female
Glycerides
Habenula
Male
Maze Learning
Mice
Mice, Inbred C57BL
Mice, Knockout
Rats
Rats, Long-Evans
Rats, Sprague-Dawley
Receptor, Cannabinoid, CB1
Spatial Memory
Stress, Psychological
