Selective inhibition of monoacylglycerol lipase is associated with passive coping behavior and attenuation of stress-induced dopamine release in the medial prefrontal cortex

被引:9
作者
Pavon, Francisco Javier [1 ,2 ,3 ,4 ]
Polis, Ilham Y. [1 ]
Stouffer, David G. [1 ]
Cravatt, Benjamin F. [5 ]
Roberto, Marisa [1 ]
Martin-Fardon, Remi [1 ]
de Fonseca, Fernando Rodriguez [2 ]
Parsons, Loren H. [1 ]
Serrano, Antonia [1 ,2 ]
机构
[1] Scripps Res Inst, Dept Neurosci, La Jolla, CA USA
[2] Hosp Reg Univ Malaga, Inst Invest Biomed Malaga IBIMA, Unidad Gest Clin Salud Mental, Malaga, Spain
[3] CIBERCV Inst Salud Carlos III, Malaga, Spain
[4] Hosp Univ Virgen Victoria, Inst Invest Biomed Malaga IBIMA, Unidad Gest Clin Corazon, Malaga, Spain
[5] Scripps Res Inst, Dept Chem, La Jolla, CA 92037 USA
来源
NEUROBIOLOGY OF STRESS | 2021年 / 14卷
关键词
2-Arachidonoylglycerol; Stress-coping behavior; Dopamine; Mouse; Microdialysis; ACID AMIDE HYDROLASE; CANNABINOID CB1 RECEPTOR; ANANDAMIDE; ANXIETY; FAAH; BLOCKADE; MODULATION; ACTIVATION; MICE; 2-ARACHIDONOYLGLYCEROL;
D O I
10.1016/j.ynstr.2021.100293
中图分类号
Q189 [神经科学];
学科分类号
071006 ;
摘要
The endocannabinoid system is involved in the regulation of the stress response, but the relative contribution of N-arachidonoylethanolamine (AEA) and 2-arachidonoylglycerol (2-AG) and their mechanisms have to be elucidated. In this study, we compared the effects of the pharmacological inhibition of the two major endocannabinoid-degrading enzymes [fatty acid amide hydrolase (FAAH) and monoacylglycerol lipase (MAGL) for AEA and 2-AG, respectively] on stress-coping [forced swim test (FST) and tail suspension test (TST)] and anxiety-like [elevated-plus maze (EPM) and light-dark test (LDT)] behaviors in wild-type and FAAH knockout mice. In vivo microdialysis estimated the effects of FAAH and MAGL inhibition on dopamine (DA) and serotonin (5-HT) levels in the medial prefrontal cortex (mPFC) during an FST. Mice were treated with PF-3845 (FAAH inhibitor), JZL184 (MAGL inhibitor), JZL195 (dual FAAH/MAGL inhibitor) or vehicle. Our data showed that PF-3845 increased latency to immobility and decreased total immobility time in FST, but no effects were observed in TST compared with vehicle-treated wild-type mice. By contrast, JZL184 decreased latency and increased immobility in TST and FST. JZL195 in wild-type mice and JZL184 in FAAH knockout mice reproduced the same passive coping behaviors as JZL184 in wild-type mice in TST and FST. In the microdialysis experiment, FST was associated with increased DA and 5-HT levels in the mPFC. However, JZL184-treated wild-type mice displayed a significant attenuation of forced swim stress-induced DA release compared with vehicle-treated wild-type mice and PF-3845-treated wild-type mice. Finally, FAAH and/or MAGL inhibitors induced robust and consistent anxiolytic-like effects in EPM and LDT. These results suggested differences between FAAH and MAGL inhibition in stress-coping behaviors. Notably, MAGL inhibition induced a consistent avoidant coping behavior and attenuated the stress-induced mPFC DA response in FST. However, more investigation is needed to elucidate the functional association between DA and 2-AG signaling pathways, and the molecular mechanism in the regulation of passive coping strategies during inescapable stress.
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页数:11
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