PPAR? regulates cholinergic-driven activity of midbrain dopamine neurons via a novel mechanism involving ?7 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 ?2 subunit (?2*-nAChRs). Nuclear peroxisome proliferator-activated receptors type-? (PPAR?) tonically regulate ?2*-nAChRs and thereby control dopamine neuron firing activity. However, it is unknown how and when PPAR? 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 ?7-nAChRs increases in the rat VTA both the tyrosine phosphorylation of the ?2 subunit of nAChRs and the levels of two PPAR? endogenous ligands in a Ca(2+)-dependent manner. Accordingly, in vivo production of endogenous PPAR? ligands, triggered by ?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? ligands are effectors of ?7-nAChRs and that their neuromodulatory properties depend on phosphorylation of ?2*-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? signaling in dopamine neurons and how behavioral output can change after modifications of this signaling pathway. Overall, the present study suggests PPAR? as new therapeutic targets for disorders associated with unbalanced dopamine-acetylcholine systems.