PPARα modulation of mesolimbic dopamine transmission rescues depression-related behaviors
Open accessAbstract
Depressive disorders cause a substantial burden for the individual and the society. Key depressive symptoms can be modeled in animals and enable the development of novel therapeutic interventions. Chronic unavoidable stress disrupts rats' competence to escape noxious stimuli and self-administer sucrose, configuring a depression model characterized by escape deficit and motivational anhedonia associated to impaired dopaminergic responses to sucrose in the nucleus accumbens shell (NAcS). Repeated treatments that restore these responses also relieve behavioral symptoms. Ventral tegmental area (VTA) dopamine neurons encode reward and motivation and are implicated in the neuropathology of depressive-like behaviors. Peroxisome proliferator-activated receptors type-α (PPARα) acutely regulate VTA dopamine neuron firing via β2 subunit-containing nicotinic acetylcholine receptors (β2*nAChRs) through phosphorylation and this effect is predictive of antidepressant-like effects. Here, by combining behavioral, electrophysiological and biochemical techniques, we studied the effects of repeated PPARα stimulation by fenofibrate on mesolimbic dopamine system. We found decreased β2*nAChRs phosphorylation levels and a switch from tonic to phasic activity of dopamine cells in the VTA, and increased phosphorylation of dopamine and cAMP-regulated phosphoprotein Mr 32,000 (DARPP-32) in the NAcS. We then investigated whether long-term fenofibrate administration to stressed rats reinstated the decreased DARPP-32 response to sucrose and whether this effect translated into antidepressant-like properties. Fenofibrate restored dopaminergic responses to appetitive stimuli, reactivity to aversive stimuli and motivation to self-administer sucrose. Overall, this study suggests PPARα as new targets for antidepressant therapies endowed with motivational anti-anhedonic properties, further supporting the role of an unbalanced mesolimbic dopamine system in pathophysiology of depressive disorders.
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Long-term activation of PPARα decreases β2-nAChR phosphorylation, increases dopamine neuron bursting, and rescues sucrose self-administration after stress.
“long-term activation of PPARα decreases β2-nAChR phosphorylation, increases dopamine neuron bursting, and rescues sucrose self-administration after stress [59].”
From The molecular and cellular mechanisms of depression: a focus on reward circuitry (2019) · cites this paper as [59]
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The molecular and cellular mechanisms of depression: a focus on reward circuitry
Fox, M. E., & Lobo, M. K. (2019) · Molecular Psychiatry · doi:10.1038/s41380-019-0415-3 · Cited by 232 · see citing works
- Authors
- Scheggi, S., Melis, M., De Felice, M., Aroni, S., Muntoni, A. L., Pelliccia, T., Gambarana, C., De Montis, M. G., & Pistis, M.
- Affiliations
- University of Siena (IT)
- University of Cagliari (IT)
- National Research Council (IT)
- Corresponding author
- Pistis, Marco
- Venue
- Neuropharmacology
- Publisher
- Elsevier BV
- Published
- 2016-11
- Volume
- 110
- Issue
- Pt A
- Pages
- 251-259
- ISSN
- 0028-3908 (ISSN-L)
- OpenAlex
- W2476078842
- Cited by
- 56
- References
- 59
- Citations by year
- 2026: 4 · 2025: 5 · 2024: 2 · 2023: 4 · 2022: 4 · 2021: 7 · 2020: 9 · 2019: 4 · 2018: 8 · 2017: 7 · 2016: 2
- FWCI
- 3.93
- Type
- journal article
- Language
- en
- Open access
- green
- hdl.handle.net
- Licence
- cc-by-nc-nd
- www.elsevier.com/tdm/userlicense/1.0/ (tdm)
- Locations
- Neuropharmacology (publishedVersion)
- PubMed (publishedVersion)
- UNICA IRIS Institutional Research Information System (University of Cagliari) (submittedVersion)
- Use Siena air (University of Siena) (submittedVersion, cc-by-nc-nd)
- Topics
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neurotransmitter Receptor Influence on Behavior
- Health Sciences › Medicine › Pharmacology › Treatment of Major Depression
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neuroscience and Neuropharmacology Research
- Keywords
- PPARα, fenofibrate, mesolimbic dopamine system, ventral tegmental area, nucleus accumbens shell, chronic stress, anhedonia, escape deficit, sucrose self-administration, nicotinic acetylcholine receptors, DARPP-32, antidepressant targets, depression
- MeSH terms
- Cyclic AMP, Animals, Antidepressive Agents, Chronic Disease, Depressive Disorder, Disease Models, Animal, Dopamine, Male, Motivation, Nucleus Accumbens, Phosphorylation, Fenofibrate, Receptors, Nicotinic, Stress, Psychological, Rats, Sprague-Dawley, Ventral Tegmental Area, Uncertainty, PPAR alpha, Dopamine and cAMP-Regulated Phosphoprotein 32, Dopaminergic Neurons, Anhedonia
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