Orphan receptor-GPR52 inverse agonist efficacy in ameliorating chronic stress-related deficits in reward motivation and phasic accumbal dopamine activity in mice
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| Názov: | Orphan receptor-GPR52 inverse agonist efficacy in ameliorating chronic stress-related deficits in reward motivation and phasic accumbal dopamine activity in mice |
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| Autori: | Zhang, Chenfeng, Kúkeľová, Diana, Sigrist, Hannes, Hengerer, Bastian, Kratzer, Ramona F, Mracek, Philipp, Omrani, Azar, von Heimendahl, Moritz, Pryce, Christopher R |
| Prispievatelia: | University of Zurich, Pryce, Christopher R |
| Zdroj: | Transl Psychiatry Translational Psychiatry, Vol 14, Iss 1, Pp 1-11 (2024) Translational Psychiatry, 14(1):363 Translational Psychiatry, 14 (1) |
| Informácie o vydavateľovi: | Springer Science and Business Media LLC, 2024. |
| Rok vydania: | 2024 |
| Predmety: | Male, 0301 basic medicine, Dopamine, 11558 Neuroscience Center Zurich, 2804 Cellular and Molecular Neuroscience, 610 Medicine & health, Neurosciences. Biological psychiatry. Neuropsychiatry, Article, Nucleus Accumbens, Receptors, G-Protein-Coupled, Learning and memory, 2738 Psychiatry and Mental Health, Mice, 03 medical and health sciences, Reward, Animals, Ventral Tegmental Area/metabolism [MeSH], Receptors, G-Protein-Coupled/metabolism [MeSH], Mice, Inbred C57BL [MeSH], Motivation/drug effects [MeSH], Nucleus Accumbens/metabolism [MeSH], Nucleus Accumbens/drug effects [MeSH], Dopamine/metabolism [MeSH], Male [MeSH], Receptors, G-Protein-Coupled/agonists [MeSH], Stress, Psychological/metabolism [MeSH], Reward [MeSH], Ventral Tegmental Area/drug effects [MeSH], 631/154/436, Disease Models, Animal [MeSH], Receptors, Dopamine D2/metabolism [MeSH], 9/74, Animals [MeSH], 64/60, 692/699/476/1414, Mice [MeSH], 631/378/1595, Receptors, Dopamine D2/agonists [MeSH], Behavior, Animal/drug effects [MeSH], article, Dopaminergic Neurons/drug effects [MeSH], Pharmacology, Motivation, 0303 health sciences, Behavior, Animal, Receptors, Dopamine D2, Depression, Dopaminergic Neurons, Ventral Tegmental Area, Mice, Inbred C57BL, Disease Models, Animal, 10054 Clinic for Psychiatry, Psychotherapy, and Psychosomatics, 2803 Biological Psychiatry, Stress, Psychological, RC321-571 |
| Popis: | Reward processing dysfunctions e.g., anhedonia, apathy, are common in stress-related neuropsychiatric disorders including depression and schizophrenia, and there are currently no established therapies. One potential therapeutic approach is restoration of reward anticipation during appetitive behavior, deficits in which co-occur with attenuated nucleus accumbens (NAc) activity, possibly due to NAc inhibition of mesolimbic dopamine (DA) signaling. Targeting NAc regulation of ventral tegmental area (VTA) DA neuron responsiveness to reward cues could involve either the direct or indirect – via ventral pallidium (VP) – pathways. One candidate is the orphan G protein-coupled receptor GPR52, expressed by DA receptor 2 NAc neurons that project to VP. In mouse brain-slice preparations, GPR52 inverse agonist (GPR52-IA) attenuated evoked inhibitory postsynaptic currents at NAc-VP neurons, which could disinhibit VTA DA neurons. A mouse model in which chronic social stress leads to reduced reward learning and effortful motivation was applied to investigate GPR52-IA behavioral effects. Control and chronically stressed mice underwent a discriminative learning test of tone-appetitive behavior-sucrose reinforcement: stress reduced appetitive responding and discriminative learning, and these anticipatory behaviors were dose-dependently reinstated by GPR52-IA. The same mice then underwent an effortful motivation test of operant behavior-tone-sucrose reinforcement: stress reduced effortful motivation and GPR52-IA dose-dependently restored it. In a new cohort, GRABDA-sensor fibre photometry was used to measure NAc DA activity during the motivation test: in stressed mice, reduced motivation co-occurred with attenuated NAc DA activity specifically to the tone that signaled reinforcement of effortful behavior, and GPR52-IA ameliorated both deficits. These findings: (1) Demonstrate preclinical efficacy of GPR52 inverse agonism for stress-related deficits in reward anticipation during appetitive behavior. (2) Suggest that GPR52-dependent disinhibition of the NAc-VP-VTA-NAc circuit, leading to increased phasic NAc DA signaling of earned incentive stimuli, could account for these clinically relevant effects. |
| Druh dokumentu: | Article Other literature type |
| Popis súboru: | application/application/pdf; s41398_024_03081_w.pdf - application/pdf |
| Jazyk: | English |
| ISSN: | 2158-3188 |
| DOI: | 10.1038/s41398-024-03081-w |
| DOI: | 10.21203/rs.3.rs-4462659/v1 |
| DOI: | 10.3929/ethz-b-000693772 |
| DOI: | 10.5167/uzh-262129 |
| Prístupová URL adresa: | https://pubmed.ncbi.nlm.nih.gov/39242529 https://doaj.org/article/c309ef7e7ee5482e8a05728ff6984619 https://repository.publisso.de/resource/frl:6519919 http://hdl.handle.net/20.500.11850/693772 |
| Rights: | CC BY NC ND CC BY |
| Prístupové číslo: | edsair.doi.dedup.....8f9d1ac0e2549d22138aa3830cde1fba |
| Databáza: | OpenAIRE |
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Nájsť tento článok vo Web of Science | Abstrakt: | Reward processing dysfunctions e.g., anhedonia, apathy, are common in stress-related neuropsychiatric disorders including depression and schizophrenia, and there are currently no established therapies. One potential therapeutic approach is restoration of reward anticipation during appetitive behavior, deficits in which co-occur with attenuated nucleus accumbens (NAc) activity, possibly due to NAc inhibition of mesolimbic dopamine (DA) signaling. Targeting NAc regulation of ventral tegmental area (VTA) DA neuron responsiveness to reward cues could involve either the direct or indirect – via ventral pallidium (VP) – pathways. One candidate is the orphan G protein-coupled receptor GPR52, expressed by DA receptor 2 NAc neurons that project to VP. In mouse brain-slice preparations, GPR52 inverse agonist (GPR52-IA) attenuated evoked inhibitory postsynaptic currents at NAc-VP neurons, which could disinhibit VTA DA neurons. A mouse model in which chronic social stress leads to reduced reward learning and effortful motivation was applied to investigate GPR52-IA behavioral effects. Control and chronically stressed mice underwent a discriminative learning test of tone-appetitive behavior-sucrose reinforcement: stress reduced appetitive responding and discriminative learning, and these anticipatory behaviors were dose-dependently reinstated by GPR52-IA. The same mice then underwent an effortful motivation test of operant behavior-tone-sucrose reinforcement: stress reduced effortful motivation and GPR52-IA dose-dependently restored it. In a new cohort, GRABDA-sensor fibre photometry was used to measure NAc DA activity during the motivation test: in stressed mice, reduced motivation co-occurred with attenuated NAc DA activity specifically to the tone that signaled reinforcement of effortful behavior, and GPR52-IA ameliorated both deficits. These findings: (1) Demonstrate preclinical efficacy of GPR52 inverse agonism for stress-related deficits in reward anticipation during appetitive behavior. (2) Suggest that GPR52-dependent disinhibition of the NAc-VP-VTA-NAc circuit, leading to increased phasic NAc DA signaling of earned incentive stimuli, could account for these clinically relevant effects. |
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| ISSN: | 21583188 |
| DOI: | 10.1038/s41398-024-03081-w |