ArticleThe Journal of neuroscience : the official journal of the Society for Neuroscience2013
PPARα regulates cholinergic-driven activity of midbrain dopamine neurons via a novel mechanism involving α7 nicotinic acetylcholine receptors.
Article in The Journal of neuroscience : the official journal of the Society for Neuroscience, 2013. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 52 papers.
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Who cites it
52 citing papers in PubMed, 91 citations in OpenAlex.
- Initial Evaluation of Fenofibrate for Efficacy in Aiding Smoking Abstinence.Nicotine & tobacco research : official journal of the Society for Research on Nicotine and Tobacco · 2016Trial
- Anti-Inflammatory Potential of Stearidonic Acid Ethanolamide in a Model of Mild Traumatic Brain Injury in Mice.Neuromolecular medicine · 2026Article
- Cannabinoid-based Pharmacology for the Management of Substance Use Disorders.Current topics in behavioral neurosciences · 2026Review
- Fenofibrate restores glutamatergic and dopaminergic homeostasis in the nucleus accumbens and reduces alcohol relapse in rats.Frontiers in pharmacology · 2026Article
- Decrypting the Possible Mechanistic Role of Fenofibrate in Alzheimer's Disease and Type 2 Diabetes: The Truth and Mystery.Journal of cellular and molecular medicine · 2025Review
- The Alpha-7 Nicotinic Receptor Positive Allosteric Modulator PNU120596 Attenuates Lipopolysaccharide-Induced Depressive-Like Behaviors and Cognitive Impairment by Regulating the PPAR-α Signaling Pathway in Mice.CNS & neurological disorders drug targets · 2025Article
- NAPE-PLD in the ventral tegmental area regulates reward events, feeding and energy homeostasis.Molecular psychiatry · 2024Article
- Role of fenofibrate in multiple sclerosis.European journal of medical research · 2024Review
- Deciphering the Role of Peroxisome Proliferator-activated Receptor α and Phosphodiesterase Type 5 Targets in Alzheimer's Disease.CNS & neurological disorders drug targets · 2024Review
- Article
- Olive oil-derived endocannabinoid-like mediators inhibit palatable food-induced reward and obesity.Communications biology · 2023Article
- New medications development for smoking cessation.Addiction neuroscience · 2023Article
- The Effect of an α-7 Nicotinic Allosteric Modulator PNU120596 and NMDA Receptor Antagonist Memantine on Depressive-like Behavior Induced by LPS in Mice: The Involvement of Brain Microglia.Brain sciences · 2022Article
- PPARα Signaling: A Candidate Target in Psychiatric Disorder Management.Biomolecules · 2022Review
- Repurposing Peroxisome Proliferator-Activated Receptor Agonists in Neurological and Psychiatric Disorders.Pharmaceuticals (Basel, Switzerland) · 2021Review
- Regulation of PPARα by APP in Alzheimer disease affects the pharmacological modulation of synaptic activity.JCI insight · 2021Article
- Roles of the Functional Interaction between Brain Cholinergic and Dopaminergic Systems in the Pathogenesis and Treatment of Schizophrenia and Parkinson's Disease.International journal of molecular sciences · 2021Review
- Review
- Different Classes of Antidepressants Inhibit the Rat α7 Nicotinic Acetylcholine Receptor by Interacting within the Ion Channel: A Functional and Structural Study.Molecules (Basel, Switzerland) · 2021Article
- Fenofibrate (a PPAR-α Agonist) Administered During Ethanol Withdrawal Reverts Ethanol-Induced Astrogliosis and Restores the Levels of Glutamate Transporter in Ethanol-Administered Adolescent Rats.Frontiers in pharmacology · 2021Article
Corrections and comments
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Authors and funding
17 authors at 6 institutions in 2 countries.
Funding
No grant is acknowledged in the PubMed record.
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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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.