Department of Integrative Physiology, University of Colorado Boulder, Boulder, Colorado, United States; Institute for Behavioral Genetics, University of Colorado Boulder, Boulder, Colorado, United States.
Department of Integrative Physiology, University of Colorado Boulder, Boulder, Colorado, United States; Institute for Behavioral Genetics, University of Colorado Boulder, Boulder, Colorado, United States; Department of Pharmaceutical Sciences, University of Colorado Anschutz Medical Campus, Aurora, Colorado, United States.
Physiol Behav. 2023 Nov 1;271:114343. doi: 10.1016/j.physbeh.2023.114343. Epub 2023 Sep 9.
Open-field activity is a commonly used measure of anxiety-related behavior in rodents. The inbred High and Low Activity strains of mice, selected for extreme differences in open-field activity, have been used as a genetic model of anxiety-related behaviors. These selected strains have been thoroughly studied through extensive behavioral testing, quantitative trait locus (QTL) mapping, whole-genome sequencing, and RNA sequencing, to uncover phenotypic and genotypic differences related to anxiety-related behavior. However, the effects of anxiolytic drugs on anxiety-related behavior in these strains have not been studied previously. This study allowed us to expand on previous findings to further characterize the anxiety-related behavior of these unique strains, using an anxiolytic drug. The goal of this study was to determine whether the treatment of adult male and female High Activity (low anxiety) and Low Activity (high anxiety) mice with diazepam, an agonist at the benzodiazepine allosteric site on the GABA receptor and a drug commonly prescribed to treat anxiety disorders in humans, led to decreases in anxiety-like defensive behavioral responses as assessed in the open-field test (OFT) and elevated plus-maze (EPM). We tested the effects of three doses of diazepam (0, 0.5, 1.0, 3.0 mg/kg, i.p.), given 30 min before behavioral testing to one High Activity strain (H2) and two Low Activity strains (L1 and L2). There was an anxiolytic effect of diazepam observed in the High Activity strain, with more entries into the open arms of the elevated plus-maze, an effect similar to that seen in common mouse strains. However, the only anxiolytic effect of diazepam seen in the Low Activity strains was a reduction in stretch attend posture (SAP). Low Activity strains also displayed freezing behavior in both the OFT and EPM. The combination of the observed freezing behavior, that was not reduced by diazepam, and the reduction in SAP seen with diazepam, suggests a more complex phenotype that includes a component of innate fear in addition to anxiety-related risk assessment behaviors. Since fear and anxiety are distinguishable traits, and both contribute to human anxiety disorders, these results provide novel insight about interpretation of previous genetic and phenotypic differences observed between the High and Low Activity strains.
旷场活动是一种常用于测量啮齿动物焦虑相关行为的方法。高活动和低活动近交系小鼠是为了在旷场活动中表现出极端差异而选择的，它们被用作与焦虑相关行为相关的遗传模型。这些选择的品系已经通过广泛的行为测试、数量性状位点 (QTL) 映射、全基因组测序和 RNA 测序进行了深入研究，以揭示与焦虑相关行为相关的表型和基因型差异。然而，以前没有研究过抗焦虑药物对这些品系焦虑相关行为的影响。本研究使用抗焦虑药物进一步扩展了以前的发现，以更深入地研究这些独特品系的焦虑相关行为。该研究的目的是确定在成年雄性和雌性高活动（低焦虑）和低活动（高焦虑）小鼠中用地西泮（GABA 受体变构部位的苯二氮䓬激动剂，一种常用于治疗人类焦虑障碍的药物）治疗是否会导致焦虑样防御行为反应减少，如旷场测试（OFT）和高架十字迷宫（EPM）评估。我们测试了三种剂量的地西泮（0、0.5、1.0、3.0mg/kg，ip）对一个高活动品系（H2）和两个低活动品系（L1 和 L2）的影响，这些药物在行为测试前 30 分钟给予。在高活动品系中观察到地西泮的抗焦虑作用，表现为更多地进入高架十字迷宫的开放臂，这与常见的小鼠品系相似。然而，地西泮在低活动品系中唯一的抗焦虑作用是减少伸展姿势（SAP）。低活动品系在旷场测试和高架十字迷宫中也表现出冻结行为。观察到的冻结行为和地西泮对 SAP 的减少的结合表明，存在一种更复杂的表型，除了焦虑相关的风险评估行为外，还包括先天恐惧的成分。由于恐惧和焦虑是可区分的特征，并且都与人类焦虑障碍有关，这些结果为解释高活动和低活动品系之间以前观察到的遗传和表型差异提供了新的见解。
