1 Department of Biopharmacy, Medical University of Lublin, Lublin, Poland.
2 Department of Pharmacology and Pharmacodynamics, Medical University of Lublin, Lublin, Poland.
J Psychopharmacol. 2019 May;33(5):558-567. doi: 10.1177/0269881118821100. Epub 2019 Jan 15.
Several lines of investigations support the idea that nicotinic acetylcholine receptors modulate neuronal pathways involved in anxiety and depression.
The purpose of this study was to determine whether 3-furan-2-yl-N-p-tolyl-acrylamide, a highly selective positive allosteric modulator of α7 nicotinic acetylcholine receptors, influences anxiety-like behaviour in mice, and to determine the modulatory activity of 3-furan-2-yl-N-p-tolyl-acrylamide on mice pretreated with either nicotine or selective α7-agonists (i.e. PNU-282987 or (2.4)-dimethoxybenzylidene anabaseine dihydrochloride).
The elevated plus maze and novelty suppressed feeding tests were selected to evaluate 3-furan-2-yl-N-p-tolyl-acrylamide and other nicotinic ligands on anxiety-like behaviour in mice.
The results indicated that: (a) 3-furan-2-yl-N-p-tolyl-acrylamide induces anxiolytic-like activity at 0.5 (elevated plus maze) and 1.0 (novelty suppressed feeding) mg/kg, respectively, after acute treatment, whereas its efficacy is increased after chronic treatments (i.e. active at 0.1 mg/kg; elevated plus maze). This is the first time showing anxiolytic-like activity elicited by 3-furan-2-yl-N-p-tolyl-acrylamide, contrary to the lack of activity for PNU-120596 (0.1 mg/kg); (b) the anxiolytic-like activity of 0.5 mg/kg 3-furan-2-yl-N-p-tolyl-acrylamide is inhibited by methyllycaconitine, a selective α7-antagonist, suggesting that α7 nicotinic acetylcholine receptors are involved in this process; (c) 0.5 mg/kg 3-furan-2-yl-N-p-tolyl-acrylamide reverses the anxiogenic effects induced by 0.1 mg/kg nicotine but not by 10.0 mg/kg PNU-282987; and (d) inactive doses of both 3-furan-2-yl-N-p-tolyl-acrylamide (0.1 mg/kg) and (2.4)-dimethoxybenzylidene anabaseine dihydrochloride (1.0 mg/kg) produce anxiolytic-like effects, suggesting drug interactions, probably synergistic.
Our findings indicated that anxiolytic-like activity is mediated by α7 nicotinic acetylcholine receptors, supporting the concept that these receptors modulate anxiety processes. The results indicating that the chronic treatment with 3-furan-2-yl-N-p-tolyl-acrylamide is more efficient than the acute treatment in eliciting anxiolytic-like activity, and that 3-furan-2-yl-N-p-tolyl-acrylamide reverses the anxiogenic effects induced by nicotine, might be of therapeutic importance during smoking cessation.
有几条研究线索支持这样一种观点，即烟碱型乙酰胆碱受体调节与焦虑和抑郁有关的神经元通路。
本研究的目的是确定 3-呋喃-2-基-N-对甲苯基丙烯酰胺是否影响焦虑样行为，3-呋喃-2-基-N-对甲苯基丙烯酰胺是一种高度选择性的α7 烟碱型乙酰胆碱受体正向变构调节剂，并确定 3-呋喃-2-基-N-对甲苯基丙烯酰胺对预先用尼古丁或选择性α7-激动剂（即 PNU-282987 或（2.4）-二甲氧基苄基基烟碱二盐酸盐）处理的小鼠的调节活性。
选择高架十字迷宫和新奇抑制摄食试验来评估 3-呋喃-2-基-N-对甲苯基丙烯酰胺和其他烟碱配体对小鼠焦虑样行为的影响。
结果表明：（a）3-呋喃-2-基-N-对甲苯基丙烯酰胺在急性处理后分别以 0.5（高架十字迷宫）和 1.0（新奇抑制摄食）mg/kg 诱导出抗焦虑样活性，而其疗效在慢性处理后增加（即 0.1mg/kg 时有效；高架十字迷宫）。这是首次显示 3-呋喃-2-基-N-对甲苯基丙烯酰胺引起的抗焦虑样活性，与 PNU-120596（0.1mg/kg）缺乏活性相反；（b）0.5mg/kg 3-呋喃-2-基-N-对甲苯基丙烯酰胺的抗焦虑样活性被选择性α7 拮抗剂甲基烟碱抑制，表明α7 烟碱型乙酰胆碱受体参与了这一过程；（c）0.5mg/kg 3-呋喃-2-基-N-对甲苯基丙烯酰胺逆转了 0.1mg/kg 尼古丁诱导的焦虑样效应，但不能逆转 10.0mg/kg PNU-282987 诱导的焦虑样效应；（d）3-呋喃-2-基-N-对甲苯基丙烯酰胺（0.1mg/kg）和（2.4）-二甲氧基苄基基烟碱二盐酸盐（1.0mg/kg）的无效剂量均产生抗焦虑样作用，提示存在药物相互作用，可能是协同作用。
我们的研究结果表明，抗焦虑样活性是由α7 烟碱型乙酰胆碱受体介导的，支持这些受体调节焦虑过程的概念。与急性处理相比，慢性处理 3-呋喃-2-基-N-对甲苯基丙烯酰胺更有效地引起抗焦虑样活性，3-呋喃-2-基-N-对甲苯基丙烯酰胺逆转尼古丁诱导的焦虑样效应，这可能在戒烟期间具有治疗意义。
