title: PPARα modulation of mesolimbic dopamine transmission rescues depression-related behaviors.
abstract: Depressive disorders cause a substantial burden for the individual and the society. Key depressive symptoms can be modeled in animals and enable the development of novel therapeutic interventions. Chronic unavoidable stress disrupts rats' competence to escape noxious stimuli and self-administer sucrose, configuring a depression model characterized by escape deficit and motivational anhedonia associated to impaired dopaminergic responses to sucrose in the nucleus accumbens shell (NAcS). Repeated treatments that restore these responses also relieve behavioral symptoms. Ventral tegmental area (VTA) dopamine neurons encode reward and motivation and are implicated in the neuropathology of depressive-like behaviors. Peroxisome proliferator-activated receptors type-α (PPARα) acutely regulate VTA dopamine neuron firing via β2 subunit-containing nicotinic acetylcholine receptors (β2*nAChRs) through phosphorylation and this effect is predictive of antidepressant-like effects. Here, by combining behavioral, electrophysiological and biochemical techniques, we studied the effects of repeated PPARα stimulation by fenofibrate on mesolimbic dopamine system. We found decreased β2*nAChRs phosphorylation levels and a switch from tonic to phasic activity of dopamine cells in the VTA, and increased phosphorylation of dopamine and cAMP-regulated phosphoprotein Mr 32,000 (DARPP-32) in the NAcS. We then investigated whether long-term fenofibrate administration to stressed rats reinstated the decreased DARPP-32 response to sucrose and whether this effect translated into antidepressant-like properties. Fenofibrate restored dopaminergic responses to appetitive stimuli, reactivity to aversive stimuli and motivation to self-administer sucrose. Overall, this study suggests PPARα as new targets for antidepressant therapies endowed with motivational anti-anhedonic properties, further supporting the role of an unbalanced mesolimbic dopamine system in pathophysiology of depressive disorders.
authors.affiliation: Department of Molecular and Developmental Medicine, University of Siena, 53100 Siena, Italy.
authors.forename: Simona
authors.initials: S
authors.lastname: Scheggi
authors.affiliation: Division of Neuroscience and Clinical Pharmacology, Department of Biomedical Sciences, University of Cagliari, 09042 Monserrato, Italy.
authors.forename: Miriam
authors.initials: M
authors.lastname: Melis
authors.affiliation: Division of Neuroscience and Clinical Pharmacology, Department of Biomedical Sciences, University of Cagliari, 09042 Monserrato, Italy.
authors.forename: Marta
authors.initials: M
authors.lastname: De Felice
authors.affiliation: Division of Neuroscience and Clinical Pharmacology, Department of Biomedical Sciences, University of Cagliari, 09042 Monserrato, Italy.
authors.forename: Sonia
authors.initials: S
authors.lastname: Aroni
authors.affiliation: Neuroscience Institute, National Research Council of Italy, Section of Cagliari, Italy.
authors.forename: Anna Lisa
authors.initials: AL
authors.lastname: Muntoni
authors.affiliation: Department of Molecular and Developmental Medicine, University of Siena, 53100 Siena, Italy.
authors.forename: Teresa
authors.initials: T
authors.lastname: Pelliccia
authors.affiliation: Department of Molecular and Developmental Medicine, University of Siena, 53100 Siena, Italy.
authors.forename: Carla
authors.initials: C
authors.lastname: Gambarana
authors.affiliation: Department of Molecular and Developmental Medicine, University of Siena, 53100 Siena, Italy.
authors.forename: Maria Graziella
authors.initials: MG
authors.lastname: De Montis
authors.affiliation: Division of Neuroscience and Clinical Pharmacology, Department of Biomedical Sciences, University of Cagliari, 09042 Monserrato, Italy; Neuroscience Institute, National Research Council of Italy, Section of Cagliari, Italy. Electronic address: mpistis@unica.it.
authors.forename: Marco
authors.initials: M
authors.lastname: Pistis
mesh_terms: D059445:Anhedonia / Q000187:drug effects / Q000502:physiology; D000818:Animals; D000928:Antidepressive Agents / Q000494:pharmacology*; D002908:Chronic Disease; D000242:Cyclic AMP / Q000378:metabolism; D003866:Depressive Disorder / Q000188:drug therapy* / Q000378:metabolism* / Q000473:pathology; D004195:Disease Models, Animal; D004298:Dopamine / Q000378:metabolism*; D051937:Dopamine and cAMP-Regulated Phosphoprotein 32 / Q000378:metabolism; D059290:Dopaminergic Neurons / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D011345:Fenofibrate / Q000494:pharmacology*; D008297:Male; D009042:Motivation / Q000187:drug effects / Q000502:physiology; D009714:Nucleus Accumbens / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D047493:PPAR alpha / Q000819:agonists* / Q000378:metabolism; D010766:Phosphorylation / Q000187:drug effects; D017207:Rats, Sprague-Dawley; D011978:Receptors, Nicotinic / Q000378:metabolism; D013315:Stress, Psychological / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology; D035501:Uncertainty; D017557:Ventral Tegmental Area / Q000187:drug effects / Q000378:metabolism / Q000473:pathology
chemical_list: D000928:Antidepressive Agents; D000242:Cyclic AMP; D004298:Dopamine; D051937:Dopamine and cAMP-Regulated Phosphoprotein 32; D011345:Fenofibrate; D047493:PPAR alpha; D011978:Receptors, Nicotinic; C497930:Ppp1r1b protein, rat
keywords: Chronic stress; Depression; Dopamine neurons; Fenofibrate (PubChem CID: 3339); Nicotinic acetylcholine receptors; Peroxisome proliferator-activated receptor alpha; Self-administration