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

Miriam Melis, Simona Scheggi, Gianfranca Carta, Camilla Madeddu, Salvatore Lecca, Antonio Luchicchi, Francesca Cadeddu, Roberto Frau, Liana Fattore, Paola Fadda, M Grazia Ennas, M Paola Castelli, Walter Fratta, Bjorn Schilstrom, Sebastiano Banni, M Graziella De Montis, Marco Pistis

Research output: Contribution to journalArticleAcademicpeer-review

Abstract

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 β2 subunit (β2*-nAChRs). Nuclear peroxisome proliferator-activated receptors type-α (PPARα) tonically regulate β2*-nAChRs and thereby control dopamine neuron firing activity. However, it is unknown how and when PPARα 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 α7-nAChRs increases in the rat VTA both the tyrosine phosphorylation of the β2 subunit of nAChRs and the levels of two PPARα endogenous ligands in a Ca(2+)-dependent manner. Accordingly, in vivo production of endogenous PPARα ligands, triggered by α7-nAChR activation, blocks in rats nicotine-induced increased firing activity of dopamine neurons and displays antidepressant-like properties. These data demonstrate that endogenous PPARα ligands are effectors of α7-nAChRs and that their neuromodulatory properties depend on phosphorylation of β2*-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/PPARα signaling in dopamine neurons and how behavioral output can change after modifications of this signaling pathway. Overall, the present study suggests PPARα as new therapeutic targets for disorders associated with unbalanced dopamine-acetylcholine systems.

Original languageEnglish
Pages (from-to)6203-11
Number of pages9
JournalJournal of Neuroscience
Volume33
Issue number14
DOIs
Publication statusPublished - 3 Apr 2013
Externally publishedYes

Cite this

Melis, Miriam ; Scheggi, Simona ; Carta, Gianfranca ; Madeddu, Camilla ; Lecca, Salvatore ; Luchicchi, Antonio ; Cadeddu, Francesca ; Frau, Roberto ; Fattore, Liana ; Fadda, Paola ; Ennas, M Grazia ; Castelli, M Paola ; Fratta, Walter ; Schilstrom, Bjorn ; Banni, Sebastiano ; De Montis, M Graziella ; Pistis, Marco. / PPARα regulates cholinergic-driven activity of midbrain dopamine neurons via a novel mechanism involving α7 nicotinic acetylcholine receptors. In: Journal of Neuroscience. 2013 ; Vol. 33, No. 14. pp. 6203-11.
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abstract = "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 β2 subunit (β2*-nAChRs). Nuclear peroxisome proliferator-activated receptors type-α (PPARα) tonically regulate β2*-nAChRs and thereby control dopamine neuron firing activity. However, it is unknown how and when PPARα 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 α7-nAChRs increases in the rat VTA both the tyrosine phosphorylation of the β2 subunit of nAChRs and the levels of two PPARα endogenous ligands in a Ca(2+)-dependent manner. Accordingly, in vivo production of endogenous PPARα ligands, triggered by α7-nAChR activation, blocks in rats nicotine-induced increased firing activity of dopamine neurons and displays antidepressant-like properties. These data demonstrate that endogenous PPARα ligands are effectors of α7-nAChRs and that their neuromodulatory properties depend on phosphorylation of β2*-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/PPARα signaling in dopamine neurons and how behavioral output can change after modifications of this signaling pathway. Overall, the present study suggests PPARα as new therapeutic targets for disorders associated with unbalanced dopamine-acetylcholine systems.",
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Melis, M, Scheggi, S, Carta, G, Madeddu, C, Lecca, S, Luchicchi, A, Cadeddu, F, Frau, R, Fattore, L, Fadda, P, Ennas, MG, Castelli, MP, Fratta, W, Schilstrom, B, Banni, S, De Montis, MG & Pistis, M 2013, 'PPARα regulates cholinergic-driven activity of midbrain dopamine neurons via a novel mechanism involving α7 nicotinic acetylcholine receptors' Journal of Neuroscience, vol. 33, no. 14, pp. 6203-11. https://doi.org/10.1523/JNEUROSCI.4647-12.2013

PPARα regulates cholinergic-driven activity of midbrain dopamine neurons via a novel mechanism involving α7 nicotinic acetylcholine receptors. / Melis, Miriam; Scheggi, Simona; Carta, Gianfranca; Madeddu, Camilla; Lecca, Salvatore; Luchicchi, Antonio; Cadeddu, Francesca; Frau, Roberto; Fattore, Liana; Fadda, Paola; Ennas, M Grazia; Castelli, M Paola; Fratta, Walter; Schilstrom, Bjorn; Banni, Sebastiano; De Montis, M Graziella; Pistis, Marco.

In: Journal of Neuroscience, Vol. 33, No. 14, 03.04.2013, p. 6203-11.

Research output: Contribution to journalArticleAcademicpeer-review

TY - JOUR

T1 - PPARα regulates cholinergic-driven activity of midbrain dopamine neurons via a novel mechanism involving α7 nicotinic acetylcholine receptors

AU - Melis, Miriam

AU - Scheggi, Simona

AU - Carta, Gianfranca

AU - Madeddu, Camilla

AU - Lecca, Salvatore

AU - Luchicchi, Antonio

AU - Cadeddu, Francesca

AU - Frau, Roberto

AU - Fattore, Liana

AU - Fadda, Paola

AU - Ennas, M Grazia

AU - Castelli, M Paola

AU - Fratta, Walter

AU - Schilstrom, Bjorn

AU - Banni, Sebastiano

AU - De Montis, M Graziella

AU - Pistis, Marco

PY - 2013/4/3

Y1 - 2013/4/3

N2 - 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 β2 subunit (β2*-nAChRs). Nuclear peroxisome proliferator-activated receptors type-α (PPARα) tonically regulate β2*-nAChRs and thereby control dopamine neuron firing activity. However, it is unknown how and when PPARα 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 α7-nAChRs increases in the rat VTA both the tyrosine phosphorylation of the β2 subunit of nAChRs and the levels of two PPARα endogenous ligands in a Ca(2+)-dependent manner. Accordingly, in vivo production of endogenous PPARα ligands, triggered by α7-nAChR activation, blocks in rats nicotine-induced increased firing activity of dopamine neurons and displays antidepressant-like properties. These data demonstrate that endogenous PPARα ligands are effectors of α7-nAChRs and that their neuromodulatory properties depend on phosphorylation of β2*-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/PPARα signaling in dopamine neurons and how behavioral output can change after modifications of this signaling pathway. Overall, the present study suggests PPARα as new therapeutic targets for disorders associated with unbalanced dopamine-acetylcholine systems.

AB - 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 β2 subunit (β2*-nAChRs). Nuclear peroxisome proliferator-activated receptors type-α (PPARα) tonically regulate β2*-nAChRs and thereby control dopamine neuron firing activity. However, it is unknown how and when PPARα 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 α7-nAChRs increases in the rat VTA both the tyrosine phosphorylation of the β2 subunit of nAChRs and the levels of two PPARα endogenous ligands in a Ca(2+)-dependent manner. Accordingly, in vivo production of endogenous PPARα ligands, triggered by α7-nAChR activation, blocks in rats nicotine-induced increased firing activity of dopamine neurons and displays antidepressant-like properties. These data demonstrate that endogenous PPARα ligands are effectors of α7-nAChRs and that their neuromodulatory properties depend on phosphorylation of β2*-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/PPARα signaling in dopamine neurons and how behavioral output can change after modifications of this signaling pathway. Overall, the present study suggests PPARα as new therapeutic targets for disorders associated with unbalanced dopamine-acetylcholine systems.

KW - Action Potentials

KW - Analysis of Variance

KW - Animals

KW - Animals, Newborn

KW - Benzamides

KW - Bridged Bicyclo Compounds

KW - Carbamates

KW - Cholinergic Agents

KW - Dihydro-beta-Erythroidine

KW - Dopaminergic Neurons

KW - Drug Interactions

KW - Enzyme Inhibitors

KW - Ethanolamines

KW - Excitatory Amino Acid Antagonists

KW - In Vitro Techniques

KW - Ligands

KW - Male

KW - PPAR alpha

KW - Patch-Clamp Techniques

KW - Pyrimidines

KW - Rats

KW - Rats, Sprague-Dawley

KW - Receptors, Nicotinic

KW - Swimming

KW - Tyrosine 3-Monooxygenase

KW - Ventral Tegmental Area

KW - alpha7 Nicotinic Acetylcholine Receptor

KW - Journal Article

KW - Research Support, Non-U.S. Gov't

U2 - 10.1523/JNEUROSCI.4647-12.2013

DO - 10.1523/JNEUROSCI.4647-12.2013

M3 - Article

VL - 33

SP - 6203

EP - 6211

JO - Journal of Neuroscience

JF - Journal of Neuroscience

SN - 0270-6474

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ER -