Fatty acid amide hydrolase inhibitors produce rapid anti-anxiety responses through amygdala long-term depression in male rodents

Fatty acid amide hydrolase inhibitors produce rapid anti-anxiety responses through amygdala long-term depression in male rodents

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J Psychiatry Neurosci 2017;42(4):230-241

Tingting Duan, PhD*; Ning Gu, MD, PhD*; Ying Wang, MD, PhD*; Feng Wang, MD, PhD; Jie Zhu, PhD; Yiru Fang, MD, PhD; Yuan Shen, MD, PhD; Jing Han, MD, PhD†; Xia Zhang, MD, PhD†

Abstract

Background: Pathological anxiety is the most common type of psychiatric disorder. The current first-line anti-anxiety treatment, selective serotonin/noradrenaline reuptake inhibitors, produces a delayed onset of action with modest therapeutic and substantial adverse effects, and long-term use of the fast-acting anti-anxiety benzodiazepines causes severe adverse effects. Inhibition of the fatty acid amide hydrolase (FAAH), the endocannabinoid N-arachidonoylethanolamine (AEA) degradative enzyme, produces anti-anxiety effects without substantial “unwanted effects” of cannabinoids, but its anti-anxiety mechanism is unclear.

Methods: We used behavioural, electrophysiological, morphological and mutagenesis strategies to assess the anti-anxiety mechanism of the FAAH inhibitors PF3845 and URB597.

Results: PF3845 exerts rapid and long-lasting anti-anxiety effects in mice exposed acutely to stress or chronically to the stress hormone corticosterone. PF3845-induced anti-anxiety effects and in vivo long-term depression (LTD) of synaptic strength at the prefrontal cortical input onto the basolateral amygdala neurons are abolished in mutant mice without CB1 cannabinoid receptors (CB1R) in brain astroglial cells, but are conserved in mice without CB1R in glutamatergic neurons. Blockade of glutamate N-methyl-d-aspartate receptors and of synaptic trafficking of glutamate AMPA receptors also abolishes PF3845-induced anti-anxiety effects in mice and LTD production in rats. URB597 produces similar anti-anxiety effects, which are abolished by blockade of LTD induction in mice.

Limitations: The determination of FAAH in which types of brain cells contribute to AEA degradation for the maintenance of amygdala interstitial AEA has yet to be determined.

Conclusion: We propose that the rapid anti-anxiety effects of FAAH inhibition are due to AEA activation of astroglial CB1R and subsequent basolateral amygdala LTD in vivo.


*Share first authorship;†share senior authorship.

Submitted June 20, 2016; Revised Aug. 26, 2016; Revised Oct. 4, 2016; Revised Oct. 12, 2016; Revised Oct. 25, 2016; Revised Oct. 30, 2016; Accepted Nov. 1, 2016; Early-released Dec. 13, 2016

Acknowledgements: This This project was supported by operating grants from the Canadian Institutes of Health Research to X. Zhang (MOP123249, MOP123256), a general grant from the National Natural Science Foundation of China to J. Han (grant no. 31371137), and an equipment grant from the Canadian Foundation for Innovation to X. Zhang. Portions of these data were included in the Innovations Award Lecture presented by X. Zhang during the CCNP meeting in Toronto, Canada, in May 2013.

Affiliations: From the University of Ottawa Institute of Mental Health Research at The Royal, Ottawa, Ont., Canada (Duan, Gu, Wang, Zhu, Zhang); the Department of Psychiatry, Xijing Hospital, Fourth Military Medical University, Xian, China (Wang); the Shanghai Mental Health Center, Shanghai Jiao Tong University School of Medicine, Shanghai, China (Fang); the Department of Psychiatry, Shanghai 10th People’s Hospital, Affiliated Hospital of Tongji University, Shanghai, China (Shen); and the Key Laboratory of Modern Teaching Technology, Shaanxi Normal University, Xi’an, Shaanxi, China (Han).

Competing interests: None declared.

Contributors: All authors designed the study. T. Duan, N. Gu, Y. Wang and F. Wang acquired the data, which all authors analyzed. T. Duan, N. Gu, Y. Yang, Y. Shen, J. Han and X. Zhang wrote the article, which all authors reviewed and approved for publication.

DOI: 10.1503/jpn.160116

Correspondence to: J. Han, Key Laboratory of Modern Teaching Technology, Shaanxi Normal University, No.199, South Chang’an Rd, Xi’an, Shaanxi, 710062, China; jinghan1991@yahoo.com; or X. Zhang, University of Ottawa Institute of Mental Health Research at the Royal, Ottawa ON K1Z  7K4, Canada; Xia.Zhang@theroyal.ca