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The dual blocker of FAAH/TRPV1 N-arachidonoylserotonin reverses the behavioral despair induced by stress in rats and modulates the HPA-axis
A. Navarria, A. Tamburella, FA. Iannotti, V. Micale, G. Camillieri, L. Gozzo, R. Verde, R. Imperatore, GM. Leggio, F. Drago, V. Di Marzo,
Language English Country England, Great Britain
Document type Journal Article, Research Support, Non-U.S. Gov't
- MeSH
- Amidohydrolases antagonists & inhibitors genetics metabolism MeSH
- Behavior, Animal drug effects MeSH
- Endocannabinoids metabolism MeSH
- Restraint, Physical MeSH
- Glycerides metabolism MeSH
- TRPV Cation Channels antagonists & inhibitors genetics metabolism MeSH
- Corticosterone blood MeSH
- Rats MeSH
- Arachidonic Acids metabolism pharmacology therapeutic use MeSH
- Brain drug effects metabolism MeSH
- Brain-Derived Neurotrophic Factor genetics metabolism MeSH
- Swimming MeSH
- Polyunsaturated Alkamides metabolism MeSH
- Rats, Wistar MeSH
- Stress, Psychological blood drug therapy metabolism MeSH
- Serotonin analogs & derivatives pharmacology therapeutic use MeSH
- Pituitary-Adrenal System MeSH
- Hypothalamo-Hypophyseal System MeSH
- Animals MeSH
- Check Tag
- Rats MeSH
- Male MeSH
- Animals MeSH
- Publication type
- Journal Article MeSH
- Research Support, Non-U.S. Gov't MeSH
In recent years, several studies have explored the involvement of the deregulation of the hypothalamus-pituitary-adrenal (HPA) axis in the pathophysiology of stress-related disorders. HPA hyper-activation as a consequence of acute/chronic stress has been found to play a major role in the neurobiological changes that are responsible for the onset of such states. Currently available medications for depression, one of the most relevant stress-related disorders, present several limitations, including a time lag for treatment response and low rates of efficacy. N-Arachidonoylserotonin (AA-5-HT), a dual blocker at fatty acid amide hydrolase (FAAH, the enzyme responsible for the inactivation of the endocannabinoid anandamide) and transient receptor potential vanilloid type-1 channel (TRPV1), produces anxiolytic-like effects in mice. The present study was designed to assess the capability of AA-5-HT to reverse the behavioral despair following exposure to stress in rats and the role of the HPA-axis. Behavioral tasks were performed, and corticosterone and endocannabinoid (anandamide and 2-arachidonoylglycerol) levels were measured in selected brain areas critically involved in the pathophysiology of stress-related disorders (medial PFC and hippocampus) under basal and stress conditions, and in response to treatment with AA-5-HT. Our data show that AA-5-HT reverses the rat behavioral despair in the forced swim test under stress conditions, and this effect is associated with the normalization of the HPA-axis deregulation that follows stress application and only in part with elevation of anandamide levels. Blockade of FAAH and TRPV1 may thus represent a novel target to design novel therapeutic strategies for the treatment of stress-related disorders.
References provided by Crossref.org
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- $a Navarria, Andrea $u Department of Clinical and Molecular Biomedicine, Section of Pharmacology and Biochemistry, University of Catania Medical School, Catania, Italy.
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- $a In recent years, several studies have explored the involvement of the deregulation of the hypothalamus-pituitary-adrenal (HPA) axis in the pathophysiology of stress-related disorders. HPA hyper-activation as a consequence of acute/chronic stress has been found to play a major role in the neurobiological changes that are responsible for the onset of such states. Currently available medications for depression, one of the most relevant stress-related disorders, present several limitations, including a time lag for treatment response and low rates of efficacy. N-Arachidonoylserotonin (AA-5-HT), a dual blocker at fatty acid amide hydrolase (FAAH, the enzyme responsible for the inactivation of the endocannabinoid anandamide) and transient receptor potential vanilloid type-1 channel (TRPV1), produces anxiolytic-like effects in mice. The present study was designed to assess the capability of AA-5-HT to reverse the behavioral despair following exposure to stress in rats and the role of the HPA-axis. Behavioral tasks were performed, and corticosterone and endocannabinoid (anandamide and 2-arachidonoylglycerol) levels were measured in selected brain areas critically involved in the pathophysiology of stress-related disorders (medial PFC and hippocampus) under basal and stress conditions, and in response to treatment with AA-5-HT. Our data show that AA-5-HT reverses the rat behavioral despair in the forced swim test under stress conditions, and this effect is associated with the normalization of the HPA-axis deregulation that follows stress application and only in part with elevation of anandamide levels. Blockade of FAAH and TRPV1 may thus represent a novel target to design novel therapeutic strategies for the treatment of stress-related disorders.
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