The dual blocker of FAAH/TRPV1 N-arachidonoylserotonin reverses the behavioral despair induced by stress in rats and modulates the HPA-axis

  • Pharmacol Res. 2014 Sep:87:151-9. doi: 10.1016/j.phrs.2014.04.014.
Andrea Navarria  1 ,  Alessandra Tamburella  1 ,  Fabio A Iannotti  2 ,  Vincenzo Micale  3 ,  Giovanni Camillieri  1 ,  Lucia Gozzo  1 ,  Roberta Verde  2 ,  Roberta Imperatore  2 ,  Gian Marco Leggio  1 ,  Filippo Drago  1 ,  Vincenzo Di Marzo  4
Affiliations
  • 1. Department of Clinical and Molecular Biomedicine, Section of Pharmacology and Biochemistry, University of Catania Medical School, Catania, Italy.
  • 2. Endocannabinoid Research Group, Institute of Biomolecular Chemistry, Consiglio Nazionale delle Ricerche, Pozzuoli, Naples, Italy.
  • 3. Department of Clinical and Molecular Biomedicine, Section of Pharmacology and Biochemistry, University of Catania Medical School, Catania, Italy; Central European Institute of Technology (CEITEC), Masaryk University, Brno, Czech Republic.
  • 4. Endocannabinoid Research Group, Institute of Biomolecular Chemistry, Consiglio Nazionale delle Ricerche, Pozzuoli, Naples, Italy. Electronic address: [email protected].
PMID: 24861565 DOI: 10.1016/j.phrs.2014.04.014
Abstract

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.

Keywords
FAAH; HPA-axis; N-Arachidonoylserotonin; Stress; TRPV1.
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