PPARα modulation of mesolimbic dopamine transmission rescues depression-related behaviors

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.