Peroxisome proliferator-activated receptors-alpha modulate dopamine cell activity through nicotinic receptors

Background: Modulation of midbrain dopamine neurons by nicotinic acetylcholine receptors (nAChRs) plays an important role in behavior, cognition, motivation, and reward. Specifically, nAChRs containing β2 subunits (β2-nAChRs) switch dopamine cells from a resting to an excited state. However, how β2-nAChRs can be modulated and thereby how dopamine firing activity is affected remains elusive. Because changes in dopamine cell activity are reflected in the dynamics of microcircuits generating altered responses to stimuli and inputs, factors regulating their state are fundamental. Among these, endogenous ligands to the nuclear receptor-transcription factor peroxisome proliferator-activated receptors type-alpha (PPARα) have been recently found to suppress nicotine-induced responses of dopamine neurons. Methods: We used both in vitro and in vivo electrophysiological techniques together with behavioral analysis to investigate on the effects of modulation of PPARα in SpragueDawley rat and C57BLJ/6 mouse dopamine neurons and their interactions with β2-nAChRs. To this aim, we took advantage of a selective reexpression of β2-nAChR exclusively in dopamine cells by stereotaxically injecting a lentiviral vector in the mouse ventral tegmental area. Results: We found that activation of PPARα decreases in vitro both dopamine cell activity and ventral tegmental area net output through negative modulation of β2-nAChRs. Additionally, PPARα activation in vivo reduces both the number of spontaneously active dopamine neurons and nicotine-induced increased locomotion. Conclusions: Our combined findings suggest PPARα ligands as important negative modulators of β2-nAChRs on dopamine neurons. Thus, PPARα ligands might prove beneficial in treating disorders in which dopamine dysfunction plays a prominent role, such as schizophrenia and nicotine addiction.