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Neurosci Biobehav Rev. 2017 May;76(Pt A):56-66. doi: 10.1016/j.neubiorev.2016.12.033.

The endocannabinoid system as a target for novel anxiolytic drugs.

Author information

1
Department of Psychiatry and Behavioral Sciences, Vanderbilt University Medical Center, Nashville, USA; Vanderbilt Brain Institute, Vanderbilt University, Nashville, USA; Department of Molecular Physiology and Biophysics, Vanderbilt University School of Medicine, Nashville, USA; Vanderbilt Kennedy Center for Human Development, Vanderbilt University Medical Center, Nashville, USA.
2
Hotchkiss Brain Institute, University of Calgary, Calgary, AB, Canada; Mathison Centre for Mental Health Research and Education, University of Calgary, Calgary, AB, Canada; Departments of Cell Biology and Anatomy and Psychiatry, University of Calgary, Calgary, AB, Canada.
3
Department of Anatomy and Neurobiology and Department of Psychiatry, University of Maryland School of Medicine, Baltimore, MD, USA.
4
Max Planck Institute of Psychiatry, Department of Stress Neurobiology & Neurogenetics, Munich, Germany.
5
Laboratory of Behavioral and Genomic Neuroscience, National Institute on Alcohol Abuse and Alcoholism, National Institutes of Health, Bethesda, MD, USA. Electronic address: holmesan@mail.nih.gov.

Abstract

The endocannabinoid (eCB) system has attracted attention for its role in various behavioral and brain functions, and as a therapeutic target in neuropsychiatric disease states, including anxiety disorders and other conditions resulting from dysfunctional responses to stress. In this mini-review, we highlight components of the eCB system that offer potential 'druggable' targets for new anxiolytic medications, emphasizing some of the less well-discussed options. We discuss how selectively amplifying eCBs recruitment by interfering with eCB-degradation, via fatty acid amide hydrolase (FAAH) and monoacylglycerol lipase (MAGL), has been linked to reductions in anxiety-like behaviors in rodents and variation in human anxiety symptoms. We also discuss a non-canonical route to regulate eCB degradation that involves interfering with cyclooxygenase-2 (COX-2). Next, we discuss approaches to targeting eCB receptor-signaling in ways that do not involve the cannabinoid receptor subtype 1 (CB1R); by targeting the CB2R subtype and the transient receptor potential vanilloid type 1 (TRPV1). Finally, we review evidence that cannabidiol (CBD), while representing a less specific pharmacological approach, may be another way to modulate eCBs and interacting neurotransmitter systems to alleviate anxiety. Taken together, these various approaches provide a range of plausible paths to developing novel compounds that could prove useful for treating trauma-related and anxiety disorders.

KEYWORDS:

Amygdala; CB1 receptor; COX-2; Cannabis; Cortisol; Dopamine; Fear; Glucocorticoid; Hippocampus; PTSD; Prefrontal cortex; Stress

PMID:
28434588
PMCID:
PMC5407316
DOI:
10.1016/j.neubiorev.2016.12.033
[Indexed for MEDLINE]
Free PMC Article

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