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 beta 2 subunits (beta 2-nAChRs) switch dopamine cells from a resting to an excited state. However, how beta 2-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 (PPAR alpha) 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 PPARa in Sprague Dawley rat and C57BLJ/6 mouse dopamine neurons and their interactions with p2-nAChRs. To this aim, we took advantage of a selective reexpression of beta 2-nAChR exclusively in dopamine cells by stereotaxically injecting a lentiviral vector in the mouse ventral tegmental area. Results: We found that activation of PPAR alpha decreases in vitro both dopamine cell activity and ventral tegmental area net output through negative modulation of beta 2-nAChRs. Additionally, PPARa activation in vivo reduces both the number of spontaneously active dopamine neurons and nicotine-induced increased locomotion. Conclusions: Our combined findings suggest PPARa ligands as important negative modulators of beta 2-nAChRs on dopamine neurons. Thus, PPARa ligands might prove beneficial in treating disorders in which dopamine dysfunction plays a prominent role, such as schizophrenia and nicotine addiction.