title: Ventral tegmental area muscarinic receptors modulate depression and anxiety-related behaviors in rats.
abstract: Cholinergic and dopaminergic mechanisms within the mesolimbic dopamine system are suggested to play a role in the manifestation of depression and anxiety-related disorders. However, despite the fact that cholinergic mechanisms in the ventral tegmental area (VTA) highly regulate dopamine activity, the role of VTA cholinergic mechanisms in depression-related behaviors is relatively unknown. Here we sought to determine whether enhancing cholinergic tone in the VTA would alter depression and anxiety-related behavior in the forced swim test (FST), elevated plus maze (EPM) and sucrose preference test (SPT). Adult Sprague Dawley male rats received VTA infusion of the acetylcholinesterase inhibitor, physostigmine (0, 1, 2μg/side), immediately prior to the FST, EPM, or SPT. Physostigmine administration increased immobility time in the FST, decreased time spent on open arms in the EPM, and decreased sucrose preference. We also examined whether activation of VTA muscarinic receptors was sufficient to alter behavior in the FST and EPM. Similar to physostigmine, VTA infusion of the muscarinic receptor agonist, pilocarpine (0, 3, 30μg/side), increased immobility time in the FST and decreased time spent on open arms in the EPM. These data suggest that enhanced VTA cholinergic tone promotes pro-depressive and anxiogenic-like effects and demonstrate that specific activation of VTA muscarinic receptors is also sufficient to induce pro-depressive and anxiogenic responses. Together, these findings reveal a novel role of VTA cholinergic, and specifically muscarinic receptor, mechanisms in mediating responses to stress and anxiety.
authors.affiliation: Department of Psychiatry, Yale School of Medicine, New Haven, CT 06511, United States.
authors.forename: Keri M
authors.initials: KM
authors.lastname: Small
authors.affiliation: Department of Psychiatry, Yale School of Medicine, New Haven, CT 06511, United States.
authors.forename: Eric
authors.initials: E
authors.lastname: Nunes
authors.affiliation: Department of Psychiatry, Yale School of Medicine, New Haven, CT 06511, United States.
authors.forename: Shannon
authors.initials: S
authors.lastname: Hughley
authors.affiliation: Department of Psychiatry, Yale School of Medicine, New Haven, CT 06511, United States; Department of Cellular and Molecular Physiology, New Haven, CT 06511, United States; Interdepartmental Neuroscience Program, Yale University, New Haven, CT 06511, United States. Electronic address: nii.addy@yale.edu.
authors.forename: Nii A
authors.initials: NA
authors.lastname: Addy
mesh_terms: D000818:Animals; D001007:Anxiety / Q000378:metabolism* / Q000523:psychology; D001522:Behavior, Animal; D002800:Cholinesterase Inhibitors / Q000494:pharmacology; D003863:Depression / Q000378:metabolism* / Q000523:psychology; D005518:Food Preferences / Q000187:drug effects; D008297:Male; D018782:Maze Learning / Q000187:drug effects; D009043:Motor Activity / Q000187:drug effects; D018721:Muscarinic Agonists / Q000494:pharmacology; D010830:Physostigmine / Q000494:pharmacology; D010862:Pilocarpine / Q000494:pharmacology; D017207:Rats, Sprague-Dawley; D011976:Receptors, Muscarinic / Q000378:metabolism*; D017557:Ventral Tegmental Area / Q000378:metabolism*
chemical_list: D002800:Cholinesterase Inhibitors; D018721:Muscarinic Agonists; D011976:Receptors, Muscarinic; D010862:Pilocarpine; D010830:Physostigmine
keywords: Acetylcholine; Anxiety; Depression; Mesolimbic dopamine system; Muscarinic receptor; Ventral tegmental area
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