PPARα regulates cholinergic-driven activity of midbrain dopamine neurons via a novel mechanism involving α7 nicotinic acetylcholine receptors.

Ventral tegmental area dopamine neurons control reward-driven learning, and their dysregulation can lead to psychiatric disorders. Tonic and phasic activity of these dopaminergic neurons depends on cholinergic tone and activation of nicotinic acetylcholine receptors (nAChRs), particularly those containing the beta 2 subunit (beta 2(star)-nAChRs). Nuclear peroxisome proliferator-activated receptors type-alpha (PPAR alpha) tonically regulate beta 2(star)-nAChRs and thereby control dopamine neuron firing activity. However, it is unknown how and when PPAR alpha endogenous ligands are synthesized by dopamine cells. Using ex vivo and in vivo electrophysiological techniques combined with biochemical and behavioral analysis, we show that activation of alpha 7-nAChRs increases in the rat VTA both the tyrosine phosphorylation of the beta 2 subunit of nAChRs and the levels of two PPAR alpha endogenous ligands in a Ca2+-dependent manner. Accordingly, in vivo production of endogenous PPAR alpha ligands, triggered by alpha 7-nAChR activation, blocks in rats nicotine-induced increased firing activity of dopamine neurons and displays antidepressant-like properties. These data demonstrate that endogenous PPAR alpha ligands are effectors of alpha 7-nAChRs and that their neuromodulatory properties depend on phosphorylation of beta 2(star)-nAChRs on VTA dopamine cells. This reveals an autoinhibitory mechanism aimed at reducing dopamine cell overexcitation engaged during hypercholinergic drive. Our results unveil important physiological functions of nAChR/PPAR alpha signaling in dopamine neurons and how behavioral output can change after modifications of this signaling pathway. Overall, the present study suggests PPAR alpha as new therapeutic targets for disorders associated with unbalanced dopamine-acetylcholine systems.