Addy N A, Nunes E J, Wickham R J
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.
Department of Psychiatry, Yale University School of Medicine, New Haven, CT 06511, USA.
Behav Brain Res. 2015 Jul 15;288:54-62. doi: 10.1016/j.bbr.2015.04.002. Epub 2015 Apr 9.
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.
最近的研究揭示了腹侧被盖区（VTA）的阶段性多巴胺（DA）活动与抑郁症啮齿动物模型中促抑郁和抗抑郁样行为反应之间的因果联系。已证明VTA中的胆碱能活动可调节阶段性DA活动，但VTA胆碱能机制在抑郁相关行为中的作用尚不清楚。本研究的目的是确定对VTA胆碱能活动进行药理学操纵是否会改变大鼠强迫游泳试验（FST）中的行为反应。在此，雄性Sprague-Dawley大鼠在FST试验前接受了全身性或VTA特异性给予乙酰胆碱酯酶抑制剂毒扁豆碱（全身性；0.06或0.125mg/kg，颅内；1或2μg/侧）、毒蕈碱型乙酰胆碱受体（AChR）拮抗剂东莨菪碱（2.4或24μg/侧）或烟碱型AChR拮抗剂美加明（3或30μg/侧）。在对照实验中，还在全身性和颅内给予胆碱能药物后检查了运动活动。全身性或直接向VTA给予毒扁豆碱显著增加了FST中的不动时间，而向背侧对照部位注入毒扁豆碱并未改变不动时间。相反，向VTA注入东莨菪碱或美加明可减少不动时间，这与抗抑郁样效应一致。最后，与东莨菪碱共同给药可阻断VTA毒扁豆碱诱导的不动增加，但与美加明共同给药则无此改变。这些数据表明，增强VTA胆碱能张力和阻断VTA AChR在FST中具有相反的作用。总之，这些发现为VTA胆碱能机制在FST行为反应中的作用提供了证据。
