Abstract
Chronic stress is the primary environmental risk factor for the development and exacerbation of affective disorders, thus understanding the neuroadaptations that occur in response to stress is a critical step in the development of novel therapeutics for depressive and anxiety disorders. Brain endocannabinoid (eCB) signaling is known to modulate emotional behavior and stress responses, and levels of the eCB 2-arachidonoylglycerol (2-AG) are elevated in response to chronic homotypic stress exposure. However, the role of 2-AG in the synaptic and behavioral adaptations to chronic stress is poorly understood. Here, we show that stress-induced development of anxiety-like behavior is paralleled by a transient appearance of low-frequency stimulation-induced, 2-AG-mediated long-term depression at GABAergic synapses in the basolateral amygdala, a key region involved in motivation, affective regulation, and emotional learning. This enhancement of 2-AG signaling is mediated, in part, via downregulation of the primary 2-AG-degrading enzyme monoacylglycerol lipase (MAGL). Acute in vivo inhibition of MAGL had little effect on anxiety-related behaviors. However, chronic stress-induced anxiety-like behavior and emergence of long-term depression of GABAergic transmission was prevented by chronic MAGL inhibition, likely via an occlusive mechanism. These data indicate that chronic stress reversibly gates eCB synaptic plasticity at inhibitory synapses in the amygdala, and in vivo augmentation of 2-AG levels prevents both behavioral and synaptic adaptations to chronic stress.
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Acknowledgements
All behavioral experiments were conducted in the Vanderbilt Neurobehavioral Core facility, and eCB analyses were conducted at the Vanderbilt Mass Spectrometry Core facility. We thank Dr DG Winder, KM Louderback, and Dr L Marnett for methodological advice and helpful discussions during the course of these studies. We thank Dr K Mackie for generous gift of MAGL antibody, which was generated with support from R01 DA011322 (KM). This work was supported by K08MH090412 (SP) and the Department of Psychiatry at the Vanderbilt University School of Medicine.
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The authors declare that, except for income received from their primary employers, no financial support or compensation has been received from any individual or corporate entity over the past 3 years for research or professional service and there are no personal financial holdings that could be perceived as constituting a potential conflict of interest.
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Sumislawski, J., Ramikie, T. & Patel, S. Reversible Gating of Endocannabinoid Plasticity in the Amygdala by Chronic Stress: A Potential Role for Monoacylglycerol Lipase Inhibition in the Prevention of Stress-Induced Behavioral Adaptation. Neuropsychopharmacol 36, 2750–2761 (2011). https://doi.org/10.1038/npp.2011.166
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DOI: https://doi.org/10.1038/npp.2011.166
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