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

Autor:	Nunes EJ; Department 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.)., Kebede N; Department 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.)., Haight JL; Department 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.)., Foster DJ; Department 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.)., Lindsley CW; Department 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.)., Conn PJ; Department 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.)., Addy NA; Department 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.
Jazyk:	angličtina
Zdroj:	The Journal of pharmacology and experimental therapeutics [J Pharmacol Exp Ther] 2023 May; Vol. 385 (2), pp. 146-156. Date of Electronic Publication: 2023 Feb 24.
DOI:	10.1124/jpet.122.001438
Abstrakt:	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. (Copyright © 2023 by The American Society for Pharmacology and Experimental Therapeutics.)
Databáze:	MEDLINE
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