Andrea Locci1, Graziano Pinna2. 1. The Psychiatric Institute, Department of Psychiatry, College of Medicine, University of Illinois at Chicago, Chicago, Illinois. 2. The Psychiatric Institute, Department of Psychiatry, College of Medicine, University of Illinois at Chicago, Chicago, Illinois. Electronic address: gpinna@uic.edu.
Abstract
BACKGROUND: The endocannabinoid and neurosteroid systems regulate emotions and stress responses. Activation of peroxisome proliferator-activated receptor (PPAR)-α by the endocannabinoid congener N-palmitoylethanolamine (PEA) regulates pathophysiological systems (e.g., inflammation, oxidative stress) and induces peripheral biosynthesis of allopregnanolone, a gamma-aminobutyric acidergic neurosteroid implicated in mood disorders. However, effects of PPAR-α on emotional behavior are poorly understood. METHODS: We studied the impact of PPAR-α activation on emotional behavior in a mouse model of posttraumatic stress disorder. Neurosteroid levels before and after PEA treatment were measured by gas chromatography-mass spectrometry in relevant brain regions of socially isolated versus group-housed mice exposed to the contextual fear conditioning test, elevated plus maze test, forced swim test, and tail suspension test. Neurosteroidogenic enzyme levels were quantified in hippocampus by Western blot. RESULTS: PEA administered in a model of conditioned contextual fear reconsolidation blockade facilitated fear extinction and fear extinction retention and induced marked antidepressive- and anxiolytic-like effects in socially isolated mice with reduced brain allopregnanolone levels. These effects were mimicked by the PPAR-α synthetic agonists, fenofibrate and GW7647, and were prevented by PPAR-α deletion, PPAR-α antagonists, and neurosteroid-enzyme inhibitors. Behavioral improvements correlated with PEA-induced upregulation of PPAR-α, neurosteroidogenic enzyme expression, and normalization of corticolimbic allopregnanolone levels. CONCLUSIONS: This evidence supports a previously unknown role for PPAR-α in behavior regulation and suggests new strategies for the treatment of neuropsychopathologies characterized by deficient neurosteroidogenesis, including posttraumatic stress disorder and major depressive disorder.
BACKGROUND: The endocannabinoid and neurosteroid systems regulate emotions and stress responses. Activation of peroxisome proliferator-activated receptor (PPAR)-α by the endocannabinoid congener N-palmitoylethanolamine (PEA) regulates pathophysiological systems (e.g., inflammation, oxidative stress) and induces peripheral biosynthesis of allopregnanolone, a gamma-aminobutyric acidergic neurosteroid implicated in mood disorders. However, effects of PPAR-α on emotional behavior are poorly understood. METHODS: We studied the impact of PPAR-α activation on emotional behavior in a mouse model of posttraumatic stress disorder. Neurosteroid levels before and after PEA treatment were measured by gas chromatography-mass spectrometry in relevant brain regions of socially isolated versus group-housed mice exposed to the contextual fear conditioning test, elevated plus maze test, forced swim test, and tail suspension test. Neurosteroidogenic enzyme levels were quantified in hippocampus by Western blot. RESULTS:PEA administered in a model of conditioned contextual fear reconsolidation blockade facilitated fear extinction and fear extinction retention and induced marked antidepressive- and anxiolytic-like effects in socially isolated mice with reduced brain allopregnanolone levels. These effects were mimicked by the PPAR-α synthetic agonists, fenofibrate and GW7647, and were prevented by PPAR-α deletion, PPAR-α antagonists, and neurosteroid-enzyme inhibitors. Behavioral improvements correlated with PEA-induced upregulation of PPAR-α, neurosteroidogenic enzyme expression, and normalization of corticolimbic allopregnanolone levels. CONCLUSIONS: This evidence supports a previously unknown role for PPAR-α in behavior regulation and suggests new strategies for the treatment of neuropsychopathologies characterized by deficient neurosteroidogenesis, including posttraumatic stress disorder and major depressive disorder.
Authors: Elliot D Mock; Mohammed Mustafa; Ozge Gunduz-Cinar; Resat Cinar; Gavin N Petrie; Vasudev Kantae; Xinyu Di; Daisuke Ogasawara; Zoltan V Varga; Janos Paloczi; Cristina Miliano; Giulia Donvito; Annelot C M van Esbroeck; Anouk M F van der Gracht; Ioli Kotsogianni; Joshua K Park; Andrea Martella; Tom van der Wel; Marjolein Soethoudt; Ming Jiang; Tiemen J Wendel; Antonius P A Janssen; Alexander T Bakker; Colleen M Donovan; Laura I Castillo; Bogdan I Florea; Jesse Wat; Helma van den Hurk; Matthias Wittwer; Uwe Grether; Andrew Holmes; Constant A A van Boeckel; Thomas Hankemeier; Benjamin F Cravatt; Matthew W Buczynski; Matthew N Hill; Pal Pacher; Aron H Lichtman; Mario van der Stelt Journal: Nat Chem Biol Date: 2020-05-11 Impact factor: 15.040
Authors: Suzanne L Pineles; Yael I Nillni; Graziano Pinna; Andrea Webb; Kimberly A Arditte Hall; Jennifer R Fonda; John Irvine; Matthew W King; Richard L Hauger; Patricia A Resick; Scott P Orr; Ann M Rasmusson Journal: Neurobiol Stress Date: 2020-05-15
Authors: Byung Kil Kim; Jennifer R Fonda; Richard L Hauger; Graziano Pinna; George M Anderson; Ivan T Valovski; Ann M Rasmusson Journal: Neurobiol Stress Date: 2020-04-18