PPARα modulation of mesolimbic dopamine transmission rescues depression-related behaviors. (November 2016)

• Record Type: Journal Article
• Authors: Scheggi, Simona; Melis, Miriam; De Felice, Marta; Aroni, Sonia; Muntoni, Anna Lisa; Pelliccia, Teresa; Gambarana, Carla; De Montis, Maria Graziella; Pistis, Marco
• Is Part Of: Neuropharmacology. Volume 110(2016) Part A
• Page Start: 251
• Page End: 259
• Publication Date: 2016-11
• Subjects: Depression -- Chronic stress -- Peroxisome proliferator-activated receptor alpha -- Dopamine neurons -- Nicotinic acetylcholine receptors -- Self-administration; Fenofibrate (PubChem CID: 3339); Neuropsychopharmacology -- Periodicals; Autonomic Agents -- Periodicals; Neuropsychopharmacologie -- Périodiques; Neuropsychopharmacology; Periodicals; Electronic journals; 615.78
• DOI: 10.1016/j.neuropharm.2016.07.024
• Languages: English
• ISSNs: 0028-3908

Abstract

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. Highlights: Chronic unavoidable stress induces depressive-like symptoms in rats. PPARα regulates dopamine transmission and is proposed to have antidepressant actions. Fenofibrate, a PPARα agonist, relieves stress-induced depressive phenotype. Fenofibrate restores the dopaminergic response to appetitive and aversive stimuli. PPARα is a new target for antidepressant therapies.