title: Ventral tegmental area cholinergic mechanisms mediate behavioral responses in the forced swim test.
abstract: Recent studies revealed a causal link between ventral tegmental area (VTA) phasic dopamine (DA) activity and pro-depressive and antidepressant-like behavioral responses in rodent models of depression. Cholinergic activity in the VTA has been demonstrated to regulate phasic DA activity, but the role of VTA cholinergic mechanisms in depression-related behavior is unclear. The goal of this study was to determine whether pharmacological manipulation of VTA cholinergic activity altered behavioral responding in the forced swim test (FST) in rats. Here, male Sprague-Dawley rats received systemic or VTA-specific administration of the acetylcholinesterase inhibitor, physostigmine (systemic; 0.06 or 0.125mg/kg, intra-cranial; 1 or 2μg/side), the muscarinic acetylcholine receptor (AChR) antagonist scopolamine (2.4 or 24μg/side), or the nicotinic AChR antagonist mecamylamine (3 or 30μg/side), prior to the FST test session. In control experiments, locomotor activity was also examined following systemic and intra-cranial administration of cholinergic drugs. Physostigmine administration, either systemically or directly into the VTA, significantly increased immobility time in FST, whereas physostigmine infusion into a dorsal control site did not alter immobility time. In contrast, VTA infusion of either scopolamine or mecamylamine decreased immobility time, consistent with an antidepressant-like effect. Finally, the VTA physostigmine-induced increase in immobility was blocked by co-administration with scopolamine, but unaltered by co-administration with mecamylamine. These data show that enhancing VTA cholinergic tone and blocking VTA AChRs has opposing effects in FST. Together, the findings provide evidence for a role of VTA cholinergic mechanisms in behavioral responses in FST.
authors: Interdepartmental Neuroscience Program, Yale School of Medicine, New Haven, CT 06520, USA; Department of Psychiatry, Yale University School of Medicine, New Haven, CT 06511, USA; Department of Cellular and Molecular Physiology, Yale University School of Medicine, New Haven, CT 06511, USA. Electronic address: nii.addy@yale.edu.
authors: N A
authors: NA
authors: Addy
authors: Department of Psychiatry, Yale University School of Medicine, New Haven, CT 06511, USA.
authors: E J
authors: EJ
authors: Nunes
authors: Interdepartmental Neuroscience Program, Yale School of Medicine, New Haven, CT 06520, USA; Department of Psychiatry, Yale University School of Medicine, New Haven, CT 06511, USA.
authors: R J
authors: RJ
authors: Wickham
mesh_terms: D000109:Acetylcholine / Q000378:metabolism*; D000818:Animals; D018680:Cholinergic Antagonists / Q000494:pharmacology; D002800:Cholinesterase Inhibitors / Q000494:pharmacology; D003866:Depressive Disorder / Q000188:drug therapy* / Q000503:physiopathology*; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D008124:Locomotion / Q000187:drug effects / Q000502:physiology; D008297:Male; D008464:Mecamylamine / Q000494:pharmacology; D009483:Neuropsychological Tests; D018733:Nicotinic Antagonists / Q000494:pharmacology; D010830:Physostigmine / Q000494:pharmacology; D017207:Rats, Sprague-Dawley; D012601:Scopolamine / Q000494:pharmacology; D013550:Swimming; D017557:Ventral Tegmental Area / Q000187:drug effects* / Q000503:physiopathology*
chemical_list: D018680:Cholinergic Antagonists; D002800:Cholinesterase Inhibitors; D018733:Nicotinic Antagonists; D008464:Mecamylamine; D010830:Physostigmine; D012601:Scopolamine; D000109:Acetylcholine
keywords: Acetylcholine; Forced swim test; Mecamylamine; Physostigmine; Scopolamine; Ventral tegmental area