Evidence map›Paper›PMID 36828630›Full record

ArticleThe Journal of pharmacology and experimental therapeutics2023

Ventral Tegmental Area M5 Muscarinic Receptors Mediate Effort-Choice Responding and Nucleus Accumbens Dopamine in a Sex-Specific Manner .

Eric J Nunes, Nardos Kebede, Joshua L Haight, Daniel J Foster, Craig W Lindsley, P Jeffrey Conn, Nii A Addy

Open access · bronzeAbstract read
PubMed Full text at PMC Publisher
In one paragraph

Article in The Journal of pharmacology and experimental therapeutics, 2023. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 9 papers.

0numbers the graph read from it
0cells of the map it votes in
9citing papers in PubMed
1.3field-weighted citation impact, top 22% of its field
1 · What the graph read from it

What it found

Each row is one number read from the abstract, on the scale the paper reported it, with its interval. Left of the dashed line favours the treatment, right favours the comparator. Under each row is the sentence it came from. New to these charts? A ten-minute tutorial.

The abstract states no effect estimate the extractor could read, or names no intervention and outcome on the map, so this paper lights no cell and moves no belief. It is still indexed, cited and linked below.

2 · The registry

The trial behind it

Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.

Neither the registry nor the abstract names a trial number. If this is a trial report, that itself is worth knowing.

3 · Its place in the literature

Who cites it

9 citing papers in PubMed, 9 citations in OpenAlex.

  1. Review
  2. Article
  3. Muscarinic Receptor Activation Preferentially Inhibits Rebound in Vulnerable Dopaminergic Neurons.The Journal of neuroscience : the official journal of the Society for Neuroscience · 2025
    Article
  4. Article
  5. Article
  6. Review
  7. Article
  8. Article
  9. Review
4 · The record

Corrections and comments

PubMed lists nothing against this paper. Absence here is not a guarantee, only a check that was made.

5 · Who and what money

Authors and funding

7 authors at 4 institutions in 1 country.

Eric J NunesDepartment of Psychiatry (E.J.N., N.K., J.L.H., N.A.A.) and Yale Tobacco Center of Regulatory Science (E.J.N.), Yale School of Medicine, New Haven, Connecticut; Department of Psychology, Quinnipiac University, Hamden, Connecticut (J.L.H.); Departments of Pharmacology (D.J.F., C.W.L., P.J.C.) and Chemistry (C.W.L.) and Vanderbilt Center for Neuroscience Drug Discovery (D.J.F., C.W.L., P.J.C.), Vanderbilt University, Nashville, Tennessee; Vanderbilt Kennedy Center, Vanderbilt University School of Medicine, Nashville, Tennessee (D.J.F., P.J.C.); and Department of Cellular and Molecular Physiology and Interdepartmental Neuroscience Program, Yale University, New Haven, Connecticut (N.A.A.).
Nardos KebedeDepartment of Psychiatry (E.J.N., N.K., J.L.H., N.A.A.) and Yale Tobacco Center of Regulatory Science (E.J.N.), Yale School of Medicine, New Haven, Connecticut; Department of Psychology, Quinnipiac University, Hamden, Connecticut (J.L.H.); Departments of Pharmacology (D.J.F., C.W.L., P.J.C.) and Chemistry (C.W.L.) and Vanderbilt Center for Neuroscience Drug Discovery (D.J.F., C.W.L., P.J.C.), Vanderbilt University, Nashville, Tennessee; Vanderbilt Kennedy Center, Vanderbilt University School of Medicine, Nashville, Tennessee (D.J.F., P.J.C.); and Department of Cellular and Molecular Physiology and Interdepartmental Neuroscience Program, Yale University, New Haven, Connecticut (N.A.A.).
Joshua L HaightDepartment of Psychiatry (E.J.N., N.K., J.L.H., N.A.A.) and Yale Tobacco Center of Regulatory Science (E.J.N.), Yale School of Medicine, New Haven, Connecticut; Department of Psychology, Quinnipiac University, Hamden, Connecticut (J.L.H.); Departments of Pharmacology (D.J.F., C.W.L., P.J.C.) and Chemistry (C.W.L.) and Vanderbilt Center for Neuroscience Drug Discovery (D.J.F., C.W.L., P.J.C.), Vanderbilt University, Nashville, Tennessee; Vanderbilt Kennedy Center, Vanderbilt University School of Medicine, Nashville, Tennessee (D.J.F., P.J.C.); and Department of Cellular and Molecular Physiology and Interdepartmental Neuroscience Program, Yale University, New Haven, Connecticut (N.A.A.).
Daniel J FosterDepartment of Psychiatry (E.J.N., N.K., J.L.H., N.A.A.) and Yale Tobacco Center of Regulatory Science (E.J.N.), Yale School of Medicine, New Haven, Connecticut; Department of Psychology, Quinnipiac University, Hamden, Connecticut (J.L.H.); Departments of Pharmacology (D.J.F., C.W.L., P.J.C.) and Chemistry (C.W.L.) and Vanderbilt Center for Neuroscience Drug Discovery (D.J.F., C.W.L., P.J.C.), Vanderbilt University, Nashville, Tennessee; Vanderbilt Kennedy Center, Vanderbilt University School of Medicine, Nashville, Tennessee (D.J.F., P.J.C.); and Department of Cellular and Molecular Physiology and Interdepartmental Neuroscience Program, Yale University, New Haven, Connecticut (N.A.A.).
Craig W LindsleyDepartment of Psychiatry (E.J.N., N.K., J.L.H., N.A.A.) and Yale Tobacco Center of Regulatory Science (E.J.N.), Yale School of Medicine, New Haven, Connecticut; Department of Psychology, Quinnipiac University, Hamden, Connecticut (J.L.H.); Departments of Pharmacology (D.J.F., C.W.L., P.J.C.) and Chemistry (C.W.L.) and Vanderbilt Center for Neuroscience Drug Discovery (D.J.F., C.W.L., P.J.C.), Vanderbilt University, Nashville, Tennessee; Vanderbilt Kennedy Center, Vanderbilt University School of Medicine, Nashville, Tennessee (D.J.F., P.J.C.); and Department of Cellular and Molecular Physiology and Interdepartmental Neuroscience Program, Yale University, New Haven, Connecticut (N.A.A.).
P Jeffrey ConnDepartment of Psychiatry (E.J.N., N.K., J.L.H., N.A.A.) and Yale Tobacco Center of Regulatory Science (E.J.N.), Yale School of Medicine, New Haven, Connecticut; Department of Psychology, Quinnipiac University, Hamden, Connecticut (J.L.H.); Departments of Pharmacology (D.J.F., C.W.L., P.J.C.) and Chemistry (C.W.L.) and Vanderbilt Center for Neuroscience Drug Discovery (D.J.F., C.W.L., P.J.C.), Vanderbilt University, Nashville, Tennessee; Vanderbilt Kennedy Center, Vanderbilt University School of Medicine, Nashville, Tennessee (D.J.F., P.J.C.); and Department of Cellular and Molecular Physiology and Interdepartmental Neuroscience Program, Yale University, New Haven, Connecticut (N.A.A.).
Nii A AddyDepartment of Psychiatry (E.J.N., N.K., J.L.H., N.A.A.) and Yale Tobacco Center of Regulatory Science (E.J.N.), Yale School of Medicine, New Haven, Connecticut; Department of Psychology, Quinnipiac University, Hamden, Connecticut (J.L.H.); Departments of Pharmacology (D.J.F., C.W.L., P.J.C.) and Chemistry (C.W.L.) and Vanderbilt Center for Neuroscience Drug Discovery (D.J.F., C.W.L., P.J.C.), Vanderbilt University, Nashville, Tennessee; Vanderbilt Kennedy Center, Vanderbilt University School of Medicine, Nashville, Tennessee (D.J.F., P.J.C.); and Department of Cellular and Molecular Physiology and Interdepartmental Neuroscience Program, Yale University, New Haven, Connecticut (N.A.A.) nii.addy@yale.edu.
Quinnipiac University · USYale University · USJohn F. Kennedy Center for the Performing Arts · USVanderbilt University · US

Funding

Ventral Tegmental Area Cholinergic Mechanisms Mediating Susceptibility to StressR01MH108663 · NIMH · YALE UNIVERSITY · PI ADDY, NII A · 2016 to 2019
$1.7M
NIMH NIH HHS R01 MH108663
6 · The paper itself

Abstract

Optimization of effort-related choices is impaired in depressive disorders. Acetylcholine (ACh) and dopamine (DA) are linked to depressive disorders, and modulation of ACh tone in the ventral tegmental area (VTA) affects mood-related behavioral responses in rats. However, it is unknown if VTA ACh mediates effort-choice behaviors. Using a task of effort-choice, rats can choose to lever press on a fixed-ratio 5 (FR5) schedule for a more-preferred food or consume freely available, less-preferred food. VTA administration of physostigmine (1 μg and 2 μg/side), a cholinesterase inhibitor, reduced FR5 responding for the more-preferred food while leaving consumption of the less-preferred food intact. VTA infusion of the M5 muscarinic receptor negative allosteric modulator VU6000181 (3 μM, 10 μM, 30 μM/side) did not affect lever pressing or chow consumption. However, VU6000181 (30 μM/side) coadministration with physostigmine (2 μg/side) attenuated physostigmine-induced decrease in lever pressing in female and male rats and significantly elevated lever pressing above vehicle baseline levels in male rats. In in vivo voltammetry experiments, VTA infusion of combined physostigmine and VU6000181 did not significantly alter evoked phasic DA release in the nucleus accumbens core (NAc) in female rats. In male rats, combined VTA infusion of physostigmine and VU6000181 increased phasic evoked DA release in the NAc compared with vehicle, physostigmine, or VU6000181 infusion alone. These data indicate a critical role and potential sex differences of VTA M5 receptors in mediating VTA cholinergic effects on effort choice behavior and regulation of DA release. SIGNIFICANCE STATEMENT: Effort-choice impairments are observed in depressive disorders, which are often treatment resistant to currently available thymoleptics. The role of ventral tegmental area (VTA) acetylcholine muscarinic M5 receptors, in a preclinical model of effort-choice behavior, is examined. Using the selective negative allosteric modulator of the M5 receptor VU6000181, we show the role of VTA M5 receptors on effort-choice and regulation of dopamine release in the nucleus accumbens core. This study supports M5 receptors as therapeutic targets for depression.

Indexed as

Nucleus AccumbensVentral Tegmental AreaAcetylcholineAnimalsDopamineFemaleMalePhysostigmineRatsRats, Sprague-DawleyReceptor, Muscarinic M5AcetylcholineDopaminePhysostigmineReceptor, Muscarinic M5

Identifiers

PMID36828630
PMCPMC10108441
OpenAlexW4321769814

What OpenQuestion holds

Textmetadata
Read underepoch 390

Registered trials

None linked

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.