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Fatty acid amide hydrolase inhibitors produce rapid anti-anxiety responses through amygdala long-term depression in male rodents.
J Psychiatry Neurosci 2017; 42(4):230-241JP

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.

Authors+Show 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).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).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).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).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).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).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).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).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).

Pub Type(s)

Journal Article
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

28234213

Citation

Duan, Tingting, et al. "Fatty Acid Amide Hydrolase Inhibitors Produce Rapid Anti-anxiety Responses Through Amygdala Long-term Depression in Male Rodents." Journal of Psychiatry & Neuroscience : JPN, vol. 42, no. 4, 2017, pp. 230-241.
Duan T, Gu N, Wang Y, et al. Fatty acid amide hydrolase inhibitors produce rapid anti-anxiety responses through amygdala long-term depression in male rodents. J Psychiatry Neurosci. 2017;42(4):230-241.
Duan, T., Gu, N., Wang, Y., Wang, F., Zhu, J., Fang, Y., ... Zhang, X. (2017). Fatty acid amide hydrolase inhibitors produce rapid anti-anxiety responses through amygdala long-term depression in male rodents. Journal of Psychiatry & Neuroscience : JPN, 42(4), pp. 230-241.
Duan T, et al. Fatty Acid Amide Hydrolase Inhibitors Produce Rapid Anti-anxiety Responses Through Amygdala Long-term Depression in Male Rodents. J Psychiatry Neurosci. 2017;42(4):230-241. PubMed PMID: 28234213.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Fatty acid amide hydrolase inhibitors produce rapid anti-anxiety responses through amygdala long-term depression in male rodents. AU - Duan,Tingting, AU - Gu,Ning, AU - Wang,Ying, AU - Wang,Feng, AU - Zhu,Jie, AU - Fang,Yiru, AU - Shen,Yuan, AU - Han,Jing, AU - Zhang,Xia, PY - 2017/2/25/pubmed PY - 2018/3/10/medline PY - 2017/2/25/entrez SP - 230 EP - 241 JF - Journal of psychiatry & neuroscience : JPN JO - J Psychiatry Neurosci VL - 42 IS - 4 N2 - 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. SN - 1488-2434 UR - https://www.unboundmedicine.com/medline/citation/28234213/Fatty_acid_amide_hydrolase_inhibitors_produce_rapid_anti_anxiety_responses_through_amygdala_long_term_depression_in_male_rodents_ L2 - https://linkinghub.elsevier.com/retrieve/pii/10.1503/jpn.160116 DB - PRIME DP - Unbound Medicine ER -