Advertisement

Stimulation of Peroxisome Proliferator-Activated Receptor-α by N-Palmitoylethanolamine Engages Allopregnanolone Biosynthesis to Modulate Emotional Behavior

  • Andrea Locci
    Affiliations
    The Psychiatric Institute, Department of Psychiatry, College of Medicine, University of Illinois at Chicago, Chicago, Illinois
    Search for articles by this author
  • Graziano Pinna
    Correspondence
    Address correspondence to Graziano Pinna, Ph.D., University of Illinois at Chicago, Department of Psychiatry, The Psychiatric Institute, 1601 West Taylor Street, Chicago, Illinois 60612.
    Affiliations
    The Psychiatric Institute, Department of Psychiatry, College of Medicine, University of Illinois at Chicago, Chicago, Illinois
    Search for articles by this author
Published:February 13, 2019DOI:https://doi.org/10.1016/j.biopsych.2019.02.006

      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.

      Keywords

      To read this article in full you will need to make a payment

      Purchase one-time access:

      Academic & Personal: 24 hour online accessCorporate R&D Professionals: 24 hour online access
      One-time access price info
      • For academic or personal research use, select 'Academic and Personal'
      • For corporate R&D use, select 'Corporate R&D Professionals'

      Subscribe:

      Subscribe to Biological Psychiatry
      Already a print subscriber? Claim online access
      Already an online subscriber? Sign in
      Institutional Access: Sign in to ScienceDirect

      References

        • Petrosino S.
        • Di Marzo V.
        The pharmacology of palmitoylethanolamide and first data on the therapeutic efficacy of some of its new formulations.
        Br J Pharmacol. 2017; 174: 1349-1365
        • Musella A.
        • Fresegna D.
        • Rizzo F.R.
        • Gentile A.
        • Bullitta S.
        • De Vito F.
        • et al.
        A novel crosstalk within the endocannabinoid system controls GABA transmission in the striatum.
        Sci Rep. 2017; 7: 7363
        • Godlewski G.
        • Offertáler L.
        • Wagner J.A.
        • Kunos G.
        Receptors for acylethanolamides-GPR55 and GPR119.
        Prostaglandins Other Lipid Mediat. 2009; 89: 105-111
        • Petrosino S.
        • Iuvone T.
        • Di Marzo V.
        N-palmitoyl-ethanolamine: Biochemistry and new therapeutic opportunities.
        Biochimie. 2009; 92: 724-727
        • Rigano D.
        • Sirignano C.
        • Taglialatela-Scafati O.
        The potential of natural products for targeting PPARα.
        Acta Pharm Sin B. 2017; 7: 427-438
        • Moreno S.
        • Farioli-Vecchioli
        • Cerù M.P.
        Immunolocalization of peroxisome proliferator-activated receptors and retinoid X receptors in the adult rat CNS.
        Neuroscience. 2004; 123: 131-145
        • Mattace Raso G.
        • Russo R.
        • Calignano A.
        • Meli R.
        Palmitoylethanolamide in CNS health and disease.
        Pharmacol Res. 2014; 86: 32-41
        • Häring M.
        • Guggenhuber S.
        • Lutz B.
        Neuronal populations mediating the effects of endocannabinoids on stress and emotionality.
        Neuroscience. 2012; 204: 145-158
        • Neumeister A.
        • Seidel J.
        • Ragen B.J.
        • Pietrzak R.H.
        Translational evidence for a role of endocannabinoids in the etiology and treatment of posttraumatic stress disorder.
        Psychoneuroendocrinology. 2014; 51: 577-584
        • Hill M.N.
        • Miller G.E.
        • Carrier E.J.
        • Gorzalka B.B.
        • Hillard C.J.
        Circulating endocannabinoids and N-acyl ethanolamines are differentially regulated in major depression and following exposure to social stress.
        Psychoneuroendocrinology. 2009; 34: 1257-1262
        • Wilker S.
        • Pfeiffer A.
        • Elbert T.
        • Ovuga E.
        • Karabatsiakis A.
        • Krumbholz A.
        • et al.
        Endocannabinoid concentrations in hair are associated with PTSD symptom severity.
        Psychoneuroendocrinology. 2016; 67: 198-206
        • Smaga I.
        • Bystrowska B.
        • Gawliński D.
        • Pomierny B.
        • Stankowicz P.
        • Filip M.
        Antidepressants and changes in concentration of endocannabinoids and N-acylethanolamines in rat brain structures.
        Neurotox Res. 2014; 26: 190-206
        • Sasso O.
        • La Rana G.
        • Vitiello S.
        • Russo R.
        • D'Agostino G.
        • Iacono A.
        • et al.
        Palmitoylethanolamide modulates pentobarbital-evoked hypnotic effect in mice: involvement of allopregnanolone biosynthesis.
        Eur Neuropsychopharmacol. 2010; 20: 195-206
        • Raso G.M.
        • Esposito E.
        • Vitiello S.
        • Iacono A.
        • Santoro A.
        • D'Agostino G.
        • et al.
        Palmitoylethanolamide stimulation induces allopregnanolone synthesis in C6 Cells and primary astrocytes: involvement of peroxisome-proliferator activated receptor-α.
        J Neuroendocrinol. 2011; 23: 591-600
        • Pinna G.
        • Uzunova V.
        • Matsumoto K.
        • Puia G.
        • Mienville J.M.
        • Costa E.
        • Guidotti A.
        Brain allopregnanolone regulates the potency of the GABA(A) receptor agonist muscimol.
        Neuropharmacology. 2000; 39: 440-448
        • Agís-Balboa R.C.
        • Pinna G.
        • Zhubi A.
        • Maloku E.
        • Veldic M.
        • Costa E.
        • Guidotti A.
        Characterization of brain neurons that express enzymes mediating neurosteroid biosynthesis.
        Proc Natl Acad Sci U S A. 2006; 103: 14602-14607
        • Agís-Balboa R.C.
        • Pinna G.
        • Pibiri F.
        • Kadriu B.
        • Costa E.
        • Guidotti A.
        Down-regulation of neurosteroid biosynthesis in corticolimbic circuits mediates social isolation-induced behavior in mice.
        Proc Natl Acad Sci U S A. 2007; 104: 18736-18741
        • Locci A.
        • Pinna G.
        Neurosteroid biosynthesis down-regulation and changes in GABAA receptor subunit composition: A biomarker axis in stress-induced cognitive and emotional impairment.
        Br J Pharmacol. 2017; 174: 3226-3241
        • Qiu Z.K.
        • Zhang G.H.
        • He J.L.
        • Ma J.C.
        • Zeng J.
        • Shen D.
        • et al.
        Free and easy wanderer plus (FEWP) improves behavioral deficits in an animal model of post-traumatic stress disorder by stimulating allopregnanolone biosynthesis.
        Neurosci Lett. 2015; 602: 162-166
        • Romeo E.
        • Ströhle A.
        • Spalletta G.
        • di Michele F.
        • Hermann B.
        • Holsboer F.
        • et al.
        Effects of antidepressant treatment on neuroactive steroids in major depression.
        Am J Psychiatry. 1998; 155: 910-913
        • Uzunova V.
        • Sheline Y.
        • Davis J.M.
        • Rasmusson A.
        • Uzunov D.P.
        • Costa E.
        • Guidotti A.
        Increase in the cerebrospinal fluid content of neurosteroids in patients with unipolar major depression who are receiving fluoxetine or fluvoxamine.
        Proc Natl Acad Sci U S A. 1998; 95: 3239-3244
        • Rasmusson A.M.
        • Pinna G.
        • Paliwal P.
        • Weisman D.
        • Gottschalk C.
        • Charney D.
        • et al.
        Decreased cerebrospinal fluid allopregnanolone levels in women with posttraumatic stress disorder.
        Biol Psychiatry. 2006; 60: 704-713
        • Agis-Balboa R.C.
        • Guidotti A.
        • Pinna G.
        5α-reductase type I expression is downregulated in the prefrontal cortex/Brodmann's area 9 (BA9) of depressed patients.
        Psychopharmacology (Berl). 2014; 231: 3569-3580
        • Pinna G.
        • Dong E.
        • Matsumoto K.
        • Costa E.
        • Guidotti A.
        In socially isolated mice, the reversal of brain allopregnanolone down-regulation mediates the anti-aggressive action of fluoxetine.
        Proc Natl Acad Sci U S A. 2003; 100: 2035-2040
        • Pibiri F.
        • Nelson M.
        • Guidotti A.
        • Costa E.
        • Pinna G.
        Decreased corticolimbic allopregnanolone expression during social isolation enhances contextual fear: A model relevant for posttraumatic stress disorder.
        Proc Natl Acad Sci U S A. 2008; 105: 5567-5572
        • Guidotti A.
        • Dong E.
        • Matsumoto K.
        • Pinna G.
        • Rasmusson A.M.
        • Costa E.
        The socially-isolated mouse: A model to study the putative role of allopregnanolone and 5alpha-dihydroprogesterone in psychiatric disorders.
        Brain Res Brain Res Rev. 2001; 37: 110-115
        • Pinna G.
        In a mouse model relevant for post-traumatic stress disorder, selective brain steroidogenic stimulants (SBSS) improve behavioral deficits by normalizing allopregnanolone biosynthesis.
        Behav Pharmacol. 2010; 2: 438-450
        • Pinna G.
        • Rasmusson A.M.
        Ganaxolone improves behavioral deficits in a mouse model of post-traumatic stress disorder.
        Front Cell Neurosci. 2014; 8: 256
        • Kanes S.
        • Colquhoun H.
        • Gunduz-Bruce H.
        • Raines S.
        • Arnold R.
        • Schacterle A.
        • et al.
        Brexanolone (SAGE-547 injection) in post-partum depression: A randomised controlled trial.
        Lancet. 2017; 390: 480-489
        • Kanes S.J.
        • Colquhoun H.
        • Doherty J.
        • Raines S.
        • Hoffmann E.
        • Rubinow D.R.
        • et al.
        Open-label, proof-of-concept study of brexanolone in the treatment of severe postpartum depression.
        Hum Psychopharmacol. 2017; 32
        • Scheggi S.
        • Melis M.
        • De Felice M.
        • Aroni S.
        • Muntoni A.L.
        • Pelliccia T.
        • et al.
        PPARα modulation of mesolimbic dopamine transmission rescues depression-related behaviors.
        Neuropharmacology. 2016; 110: 251-259
        • Pinna G.
        • Agis-Balboa R.C.
        • Zhubi A.
        • Matsumoto K.
        • Grayson D.R.
        • Costa E.
        • Guidotti A.
        Imidazenil and diazepam increase locomotor activity in mice exposed to protracted social isolation.
        Proc Natl Acad Sci U S A. 2006; 103: 4275-4280
        • Can A.
        • Dao D.T.
        • Arad M.
        • Terrillion C.E.
        • Piantadosi S.C.
        • Gould T.D.
        The mouse forced swim test.
        J Vis Exp. 2012; 59: e3638
        • Can A.
        • Dao D.T.
        • Terrillion C.E.
        • Piantadosi S.C.
        • Bhat S.
        • Gould T.D.
        The tail suspension test.
        J Vis Exp. 2012; 59: e3769
        • Uzunov D.P.
        • Cooper T.B.
        • Costa E.
        • Guidotti A.
        Fluoxetine-elicited changes in brain neurosteroid content measured by negative ion mass fragmentography.
        Proc Natl Acad Sci U S A. 1996; 93: 12599-12604
        • Tremolizzo L.
        • Doueiri M.S.
        • Dong E.
        • Grayson D.R.
        • Davis J.
        • Pinna G.
        • et al.
        Valproate corrects the schizophrenia-like epigenetic behavioral modifications induced by methionine in mice.
        Biol Psychiatry. 2005; 57: 500-509
        • Locci A.
        • Geoffroy P.
        • Miesch M.
        • Mensah-Nyagan A.G.
        • Pinna G.
        Social isolation in early versus late adolescent mice is associated with persistent behavioral deficits that can be improved by neurosteroid-based treatment.
        Front Cell Neurosci. 2017; 11: 208
        • Le Foll B.
        • Di Ciano P.
        • Panlilio L.V.
        • Goldberg S.R.
        • Ciccocioppo R.
        Peroxisome proliferator-activated receptor (PPAR) agonists as promising new medications for drug addiction: Preclinical evidence.
        Curr Drug Targets. 2013; 14: 768-776
        • Blednov Y.A.
        • Black M.
        • Benavidez J.M.
        • Stamatakis E.E.
        • Harris R.A.
        PPAR agonists: II. Fenofibrate and tesaglitazar alter behaviors related to voluntary alcohol consumption.
        Alcohol Clin Exp Res. 2016; 40: 563-571
        • Song L.
        • Wang H.
        • Wang Y.J.
        • Wang J.L.
        • Zhu Q.
        • Wu F.
        • et al.
        Hippocampal PPARα is a novel therapeutic target for depression and mediates the antidepressant actions of fluoxetine in mice.
        Br J Pharmacol. 2018; 175: 2968-2987
        • Jiang Bo
        • Wang Y.J.
        • Wang H.
        • Song L.
        • Huang C.
        • Zhu Q.
        • et al.
        Antidepressant-like effects of fenofibrate in mice via the hippocampal brain-derived neurotrophic factor signaling pathway.
        Br J Pharmacol. 2017; 174: 177-194
        • Nin M.S.
        • Martinez L.A.
        • Pibiri F.
        • Nelson M.
        • Pinna G.
        Neurosteroids reduce social isolation-induced behavioral deficits: A proposed link with neurosteroid-mediated upregulation of BDNF expression.
        Front Endocrinol (Lausanne). 2011; 2: 73
        • Puligheddu M.
        • Melis M.
        • Pillolla G.
        • Milioli G.
        • Parrino L.
        • Terzano G.M.
        • et al.
        Rationale for an adjunctive therapy with fenofibrate in pharmacoresistant nocturnal frontal lobe epilepsy.
        Epilepsia. 2017; 58: 1762-1770
        • O’Sullivan S.E.
        Cannabinoids go nuclear: Evidence for activation of peroxisome proliferator-activated receptors.
        Br J Pharmacol. 2007; 152: 576-582
        • Kinden R.
        • Zhang X.
        Cannabinoids & stress: Impact of HU-210 on behavioral tests of anxiety in acutely stressed mice.
        Behav Brain Res. 2015; 284: 225-230
        • Morena M.
        • Patel S.
        • Bains J.S.
        • Hill M.N.
        Neurobiological interactions Between Stress and the Endocannabinoid System.
        Neuropsychopharmacology. 2016; 41: 80-102
        • Umathe S.N.
        • Manna S.S.
        • Jain N.S.
        Involvement of endocannabinoids in antidepressant and anti-compulsive effect of fluoxetine in mice.
        Behav Brain Res. 2011; 223: 125-134
        • Dlugos A.
        • Childs E.
        • Stuhr K.L.
        • Hillard C.J.
        • de Wit H.
        Acute stress increases circulating anandamide and other N-acylethanolamines in healthy humans.
        Neuropsychopharmacology. 2012; 37: 2416-2427
        • Hill M.N.
        • McLaughlin R.J.
        • Morrish A.C.
        • Viau V.
        • Floresco S.B.
        • Hillard C.J.
        • Gorzalka B.B.
        Suppression of amygdalar endocannabinoid signaling by stress contributes to activation of the hypothalamic-pituitary-adrenal axis.
        Neuropsychopharmacology. 2009; 34: 2733-2745
        • Holman E.A.
        • Guijarro A.
        • Lim J.
        • Piomelli D.
        Effects of acute stress on cardiac endocannabinoids, lipogenesis, and inflammation in rats.
        Psychosom Med. 2014; 76: 20-28
        • Ghazizadeh-Hashemi M.
        • Ghajar A.
        • Shalbafan M.R.
        • Ghazizadeh-Hashemi F.
        • Afarideh M.
        • Malekpour F.
        • et al.
        Palmitoylethanolamide as adjunctive therapy in major depressive disorder: A double-blind, randomized and placebo-controlled trial.
        J Affect Disord. 2018; 232: 127-133
        • Heyman E.
        • Gamelin F.X.
        • Goekint M.
        • Piscitelli F.
        • Roelands B.
        • Leclair E.
        • et al.
        Intense exercise increases circulating endocannabinoid and BDNF levels in humans-possible implications for reward and depression.
        Psychoneuroendocrinology. 2012; 37: 844-851
        • Scioli-Salter E.
        • Forman D.E.
        • Otis J.D.
        • Tun C.
        • Allsup K.
        • Marx C.E.
        • et al.
        Potential neurobiological benefits of exercise in chronic pain and posttraumatic stress disorder: Pilot study.
        J Rehabil Res Dev. 2016; 53: 95-106
        • Hillard C.J.
        Stress regulates endocannabinoid-CB1 receptor signaling.
        Semin Immunol. 2014; 26: 380-388
        • Katona I.
        Endocannabinoid receptors: CNS localization of the CB1 cannabinoid receptor.
        Curr Top Behav Neurosci. 2009; 1: 65-86
        • Janero D.R.
        Cannabinoid-1 receptor (CB1R) blockers as medicines: Beyond obesity and cardiometabolic disorders to substance abuse/drug addiction with CB1R neutral antagonists.
        Expert Opin Emerg Drugs. 2012; 17: 17-29
        • Pinna G.
        • Agis-Balboa R.C.
        • Pibiri F.
        • Nelson M.
        • Guidotti A.
        • Costa E.
        Neurosteroid biosynthesis regulates sexually dimorphic fear and aggressive behavior in mice.
        Neurochem Res. 2008; 33: 1990-2007
        • Vyklicky V.
        • Smejkalova T.
        • Krausova B.
        • Balik A.
        • Korinek M.
        • Borovska J.
        • et al.
        Preferential inhibition of tonically over phasically activated NMDA receptors by pregnane derivatives.
        J Neurosci. 2016; 36: 2161-2175
        • Dang Y.H.
        • Ma X.C.
        • Zhang J.C.
        • Ren Q.
        • Wu J.
        • Gao C.G.
        • Hashimoto K.
        Targeting of NMDA receptors in the treatment of major depression.
        Curr Pharm Des. 2014; 20: 5151-5159
        • Jafarinia M.
        • Afarideh M.
        • Tafakhori A.
        • Arbabi M.
        • Ghajar A.
        • Noorbala A.A.
        • et al.
        Efficacy and safety of oral ketamine versus diclofenac to alleviate mild to moderate depression in chronic pain patients: A double-blind, randomized, controlled trial.
        J Affect Disord. 2016; 204: 1-8
        • Guida F.
        • Boccella S.
        • Iannotta M.
        • De Gregorio D.
        • Giordano C.
        • Belardo C.
        • et al.
        Palmitoylethanolamide reduces neuropsychiatric behaviors by restoring cortical electrophysiological activity in a mouse model of mild traumatic brain injury.
        Front Pharmacol. 2017; 8: 95
        • Scuderi C.
        • Bronzuoli M.R.
        • Facchinetti R.
        • Pace L.
        • Ferraro L.
        • Broad K.D.
        • et al.
        Ultramicronized palmitoylethanolamide rescues learning and memory impairments in a triple transgenic mouse model of Alzheimer’s disease by exerting anti-inflammatory and neuroprotective effects.
        Transl Psychiatry. 2018; 8: 32
        • Dong E.
        • Matsumoto K.
        • Uzunova V.
        • Sugaya I.
        • Takahata H.
        • Nomura H.
        • et al.
        Brain 5alpha-dihydroprogesterone and allopregnanolone synthesis in a mouse model of protracted social isolation.
        Proc Natl Acad Sci U S A. 2001; 98: 2849-2854
        • Rasmusson A.M.
        • King M.W.
        • Valovski I.
        • Gregor K.
        • Scioli-Salter E.
        • Pineles S.L.
        • et al.
        Relationships between cerebrospinal fluid GABAergic neurosteroid levels and symptom severity in men with PTSD.
        Psychoneuroendocrinology. 2018; 102: 95-104
        • Rakhshandehroo M.
        • Hooiveld G.
        • Müller M.
        • Kersten S.
        Comparative analysis of gene regulation by the transcription factor PPARalpha between mouse and human.
        PLoS One. 2009; 4: e6796
        • McMullen P.D.
        • Bhattacharya S.
        • Woods C.G.
        • Sun B.
        • Yarborough K.
        • Ross S.M.
        • et al.
        A map of the PPARα transcription regulatory network for primary human hepatocytes.
        Chem Biol Interact. 2014; 209: 14-24
        • Scuderi C.
        • Esposito G.
        • Blasio A.
        • Valenza M.
        • Arietti P.
        • Steardo Jr., L.
        • et al.
        Palmitoylethanolamide counteracts reactive astrogliosis induced by β-amyloid peptide.
        J Cell Mol Med. 2011; 15: 2664-2674
        • Lo Verme J.
        • Fu J.
        • Astarita G.
        • La Rana G.
        • Russo R.
        • Calignano A.
        • Piomelli D.
        The nuclear receptor peroxisome proliferator-activated receptor-alpha mediates the anti-inflammatory actions of palmitoylethanolamide.
        Mol Pharmacol. 2005; 67: 15-19
        • Ledwith B.J.
        • Manam S.
        • Troilo P.
        • Joslyn D.J.
        • Galloway S.M.
        • Nichols W.W.
        Activation of immediate-early gene expression by peroxisome proliferators in vitro.
        Mol Carcinog. 1993; 8: 20-27
        • Aspesi D.
        • Pinna G.
        Could a blood test for PTSD be on the horizon?.
        Expert Rev Proteomics. 2018; 15: 983-1006
        • Aspesi D.
        • Pinna G.
        Animal models of post-traumatic stress disorder and novel treatment targets.
        Behav Pharmacol. 2019; 30: 130-150
        • Locci A.
        • Pinna G.
        Social isolation as a promising animal model of PTSD comorbid suicide: Neurosteroids and cannabinoids as possible treatment options.
        Prog Neuropsychopharmacol Biol Psychiatry. 2018; 92: 243-259

      CHORUS Manuscript

      View Open Manuscript