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Therapeutic endocannabinoid augmentation for mood and anxiety disorders: comparative profiling of FAAH, MAGL and dual inhibitors.
Transl Psychiatry. 2018 04 26; 8(1):92.TP

Abstract

Recent studies have demonstrated anxiolytic potential of pharmacological endocannabinoid (eCB) augmentation approaches in a variety of preclinical models. Pharmacological inhibition of endocannabinoid-degrading enzymes, such as fatty acid amide hydrolase (FAAH) and monoacylglycerol lipase (MAGL), elicit promising anxiolytic effects in rodent models with limited adverse behavioral effects, however, the efficacy of dual FAAH/MAGL inhibition has not been investigated. In the present study, we compared the effects of FAAH (PF-3845), MAGL (JZL184) and dual FAAH/MAGL (JZL195) inhibitors on (1) anxiety-like behaviors under non-stressed and stressed conditions, (2) locomotor activity and body temperature, (3) lipid levels in the brain and (4) cognitive functions. Behavioral analysis showed that PF-3845 or JZL184, but not JZL195, was able to prevent restraint stress-induced anxiety in the light-dark box assay when administered before stress exposure. Moreover, JZL195 treatment was not able to reverse foot shock-induced anxiety-like behavior in the elevated zero maze or light-dark box. JZL195, but not PF-3845 or JZL184, decreased body temperature and increased anxiety-like behavior in the open-field test. Overall, JZL195 did not show anxiolytic efficacy and the effects of JZL184 were more robust than that of PF-3845 in the models examined. These results showed that increasing either endogenous AEA or 2-AG separately produces anti-anxiety effects under stressful conditions but the same effects are not obtained from simultaneously increasing both AEA and 2-AG.

Authors+Show Affiliations

Department of Psychiatry and Behavioral Sciences, Vanderbilt University Medical Center, Nashville, TN, USA. gaurav.bedse@vumc.org.Department of Psychiatry and Behavioral Sciences, Vanderbilt University Medical Center, Nashville, TN, USA. Vanderbilt Brain Institute, Vanderbilt University, Nashville, TN, USA.Department of Psychiatry and Behavioral Sciences, Vanderbilt University Medical Center, Nashville, TN, USA.Department of Psychiatry and Behavioral Sciences, Vanderbilt University Medical Center, Nashville, TN, USA.Department of Psychiatry and Behavioral Sciences, Vanderbilt University Medical Center, Nashville, TN, USA.Departments of Biochemistry, Chemistry, and Pharmacology, A.B. Hancock Jr. Memorial Laboratory for Cancer Research, Vanderbilt Institute of Chemical Biology, Vanderbilt University School of Medicine, Nashville, TN, USA.H. Lundbeck A/S, Copenhagen, Denmark.Departments of Biochemistry, Chemistry, and Pharmacology, A.B. Hancock Jr. Memorial Laboratory for Cancer Research, Vanderbilt Institute of Chemical Biology, Vanderbilt University School of Medicine, Nashville, TN, USA.Department of Psychiatry and Behavioral Sciences, Vanderbilt University Medical Center, Nashville, TN, USA. Vanderbilt Brain Institute, Vanderbilt University, Nashville, TN, USA. Department of Molecular Physiology and Biophysics, Vanderbilt University School of Medicine, Nashville, TN, USA.

Pub Type(s)

Journal Article
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

29695817

Citation

Bedse, Gaurav, et al. "Therapeutic Endocannabinoid Augmentation for Mood and Anxiety Disorders: Comparative Profiling of FAAH, MAGL and Dual Inhibitors." Translational Psychiatry, vol. 8, no. 1, 2018, p. 92.
Bedse G, Bluett RJ, Patrick TA, et al. Therapeutic endocannabinoid augmentation for mood and anxiety disorders: comparative profiling of FAAH, MAGL and dual inhibitors. Transl Psychiatry. 2018;8(1):92.
Bedse, G., Bluett, R. J., Patrick, T. A., Romness, N. K., Gaulden, A. D., Kingsley, P. J., Plath, N., Marnett, L. J., & Patel, S. (2018). Therapeutic endocannabinoid augmentation for mood and anxiety disorders: comparative profiling of FAAH, MAGL and dual inhibitors. Translational Psychiatry, 8(1), 92. https://doi.org/10.1038/s41398-018-0141-7
Bedse G, et al. Therapeutic Endocannabinoid Augmentation for Mood and Anxiety Disorders: Comparative Profiling of FAAH, MAGL and Dual Inhibitors. Transl Psychiatry. 2018 04 26;8(1):92. PubMed PMID: 29695817.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Therapeutic endocannabinoid augmentation for mood and anxiety disorders: comparative profiling of FAAH, MAGL and dual inhibitors. AU - Bedse,Gaurav, AU - Bluett,Rebecca J, AU - Patrick,Toni A, AU - Romness,Nicole K, AU - Gaulden,Andrew D, AU - Kingsley,Philip J, AU - Plath,Niels, AU - Marnett,Lawrence J, AU - Patel,Sachin, Y1 - 2018/04/26/ PY - 2017/10/02/received PY - 2018/02/22/accepted PY - 2017/12/28/revised PY - 2018/4/27/entrez PY - 2018/4/27/pubmed PY - 2018/12/12/medline SP - 92 EP - 92 JF - Translational psychiatry JO - Transl Psychiatry VL - 8 IS - 1 N2 - Recent studies have demonstrated anxiolytic potential of pharmacological endocannabinoid (eCB) augmentation approaches in a variety of preclinical models. Pharmacological inhibition of endocannabinoid-degrading enzymes, such as fatty acid amide hydrolase (FAAH) and monoacylglycerol lipase (MAGL), elicit promising anxiolytic effects in rodent models with limited adverse behavioral effects, however, the efficacy of dual FAAH/MAGL inhibition has not been investigated. In the present study, we compared the effects of FAAH (PF-3845), MAGL (JZL184) and dual FAAH/MAGL (JZL195) inhibitors on (1) anxiety-like behaviors under non-stressed and stressed conditions, (2) locomotor activity and body temperature, (3) lipid levels in the brain and (4) cognitive functions. Behavioral analysis showed that PF-3845 or JZL184, but not JZL195, was able to prevent restraint stress-induced anxiety in the light-dark box assay when administered before stress exposure. Moreover, JZL195 treatment was not able to reverse foot shock-induced anxiety-like behavior in the elevated zero maze or light-dark box. JZL195, but not PF-3845 or JZL184, decreased body temperature and increased anxiety-like behavior in the open-field test. Overall, JZL195 did not show anxiolytic efficacy and the effects of JZL184 were more robust than that of PF-3845 in the models examined. These results showed that increasing either endogenous AEA or 2-AG separately produces anti-anxiety effects under stressful conditions but the same effects are not obtained from simultaneously increasing both AEA and 2-AG. SN - 2158-3188 UR - https://www.unboundmedicine.com/medline/citation/29695817/Therapeutic_endocannabinoid_augmentation_for_mood_and_anxiety_disorders:_comparative_profiling_of_FAAH_MAGL_and_dual_inhibitors_ L2 - https://doi.org/10.1038/s41398-018-0141-7 DB - PRIME DP - Unbound Medicine ER -