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Low Dose Nicotine and Antagonism of β2 Subunit Containing Nicotinic Acetylcholine Receptors Have Similar Effects on Affective Behavior in Mice

机译：低剂量尼古丁和β2亚基含对小鼠情感行为烟碱乙酰胆碱受体有类似的效果的拮抗作用

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Nicotine leads to both activation and desensitization (inactivation) of nicotinic acetylcholine receptors (nAChRs). This study tested the hypothesis that nicotine and a selective antagonist of β2*nAChRs would have similar effects on affective behavior. Adult C57BL/6J male mice were tested in a conditioned emotional response (CER) assay which evaluates the ability of an aversive stimulus to inhibit goal-directed behavior. Mice lever-pressed for a saccharin reinforcer according to a variable schedule of reinforcement during sessions in which two presentations of a compound light/tone conditioned stimulus (CS) co-terminated with a 0.1 or 0.3 mA, 0.5 s footshock unconditioned stimulus (US). During testing in the absence of the US, mice received doses of i.p. nicotine (0, 0.0032, 0.01, 0.032, 0.1 mg/kg) or a selective β2 subunit containing nAChR (β2*nAChR) antagonist dihydro-beta-erythroidine (0, 0.1, 0.3, 1.0, 3.0 mg/kg DHβE). There was a dose-dependent effect of nicotine revealing that only low doses (0.01, 0.032 mg/kg) increased CER suppression ratios (SR) in these mice. DHβE also dose-dependently increased SR at the 3 mg/kg dose. In ethological measures of fear−/anxiety-like behavior, these doses of nicotine and DHβE significantly reduced digging behavior in a marble burying task and 0.3 mg/kg DHβE promoted open-arm activity in the elevated plus maze. Doses of nicotine and DHβE that altered affective behavior had no effect on locomotor activity. Similar to previous reports with anxiolytic drugs, low dose nicotine and DHβE reversed SR in a CER assay, decreased digging in a marble burying assay and increased open arm activity in the elevated plus maze. This study provides evidence that inactivation of β2*nAChRs reduces fear-like and anxiety-like behavior in rodents and suggests that smokers may be motivated to smoke in part to desensitize their β2*nAChRs. These data further identify β2*nAChR antagonism as a potential therapeutic strategy for relief of negative affect and anxiety.
机译：尼古丁可导致烟碱乙酰胆碱受体（nAChRs）活化和脱敏（失活）。这项研究检验了以下假设：尼古丁和β2* nAChRs的选择性拮抗剂对情感行为的影响类似。在条件化情绪反应（CER）分析中测试了成年C57BL / 6J雄性小鼠，该分析评估了厌恶刺激抑制目标定向行为的能力。小鼠在会话期间根据可变的强化时间表按糖精增强剂进行杠杆按压，在该会话中，两次演示复合的轻/音调条件刺激（CS）与0.1或0.3 mA，0.5 s休克无条件刺激（US）共同终止。在没有美国的情况下进行测试期间，小鼠接受了腹膜内注射剂量。尼古丁（0、0.0032、0.01、0.032、0.1 mg / kg）或含有nAChR（β2* nAChR）拮抗剂二氢β-类红血球碱（0、0.1、0.3、1.0、3.0 mg / kgDHβE）的选择性β2亚基。尼古丁具有剂量依赖性效应，表明这些小鼠中只有低剂量（0.01，0.032 mg / kg）会提高CER抑制率（SR）。 DHβE在3 mg / kg剂量下也剂量依赖性地增加SR。在恐惧/焦虑样行为的行为学测量中，这些剂量的尼古丁和DHβE大大降低了大理石掩埋任务中的挖掘行为，0.3 mg / kgDHβE促进了高架迷宫中的开臂活动。改变情感行为的尼古丁和DHβE剂量对运动能力没有影响。与先前关于抗焦虑药的报道相似，在CER分析中低剂量尼古丁和DHβE逆转了SR，在大理石掩埋分析中减少了挖掘，并在高架迷宫中增加了开臂活动。这项研究提供的证据表明，β2* nAChRs的失活减少了啮齿动物的恐惧感和焦虑样行为，并表明吸烟者可能被吸烟的一部分动机是使他们的β2* nAChRs脱敏。这些数据进一步确定了β2* nAChR拮抗作用是减轻负面影响和焦虑的潜在治疗策略。

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