Broward Health Medical Center, 3100 SW 62nd Avenue, Miami, FL, 33155, USA.
City University of New York, CUNY Neuroscience Collaborative, The Graduate Center, 365 Fifth Ave., New York, NY, 10016, USA.
Behav Brain Res. 2020 Apr 6;383:112522. doi: 10.1016/j.bbr.2020.112522. Epub 2020 Jan 30.
Impulsivity and anxiety are psychological traits involved in many aspects of the drug addiction cycle. However, few preclinical models exist for examining both impulsive and anxiety patterns. In the current study, we investigated whether 6 generation rats selectively bred for high anxiety (HAn)-like behavior would display amphetamine (AMPH) hyperactivity. In the same generational line, we also determined if HAn animals would display impulsivity in an operant task. Filial 5 male Long Evans rats phenotyped as HAn and low anxiety (LAn) were tested on the elevated plus maze (EPM) and in locomotor chambers following a low dose of AMPH (0.5 mg/kg, IP). Next, a separate group of F5 animals was exposed to a differential reinforcement of low rate of responding (DRL: 30 s) operant schedule to assess impulsivity. Postmortem, 5-HT1A and α2 adrenergic receptor protein levels were measured in the medial prefrontal cortex (mPFC), nucleus accumbens (NAc) core and shell, and α2 adrenergic counts were assessed in the locus coeruleus (LC), and the paraventricular nucleus (PVN) of the hypothalamus. F5 outbred HAn rats had decreased percent open arm time and entries on the EPM and elevated AMPH-induced locomotion. In the DRL, HAn rats displayed an impulsive profile, they attained fewer total rewards, had more inter-response times, and showed greater burst ratios. We found that HAn rats had a higher number of 5-HT1A receptor immunostained cells in the mPFC but were not different than LAn in NAc core or shell. By contrast, levels of the α2 adrenergic receptor protein were no different in the mPFC while HAn rats had greater levels in the LC and lower levels in the PVN. Overall, these data further validate our outbred trait anxiety rats: HAn males show anxiety-like behavior, AMPH hypersensitivity, greater impulsivity, and varying levels of limbic and midbrain 5-HT1A and α2 adrenergic receptor proteins.
冲动和焦虑是涉及药物成瘾周期多个方面的心理特征。然而，目前很少有临床前模型可用于研究冲动和焦虑模式。在本研究中，我们探讨了是否经过 6 代选择性培育以产生高焦虑（HAn）样行为的大鼠会表现出安非他命（AMPH）过度活跃。在同一世代线中，我们还确定 HAn 动物是否会在操作性任务中表现出冲动。表型为 HAn 和低焦虑（LAn）的第 5 代雄性长爪沙鼠被测试在高架十字迷宫（EPM）上的行为和在低剂量 AMPH（0.5mg/kg，IP）后在运动室中的行为。接下来，一组单独的 F5 动物被暴露于差异强化低反应率（DRL：30s）操作性时间表，以评估冲动。死后，测量中前额叶皮层（mPFC）、伏隔核（NAc）核心和壳以及蓝斑核（LC）和下丘脑室旁核（PVN）中的 5-HT1A 和 α2 肾上腺素能受体蛋白水平。F5 远交 HAn 大鼠的 EPM 开放臂时间和进入次数减少，AMPH 诱导的运动增加。在 DRL 中，HAn 大鼠表现出冲动行为，他们获得的总奖励更少，反应时间间隔更多，爆发比更大。我们发现，HAn 大鼠的 mPFC 中 5-HT1A 受体免疫染色细胞数量更多，但在 NAc 核心或壳中与 LAn 无差异。相比之下，mPFC 中的 α2 肾上腺素能受体蛋白水平没有差异，而 HAn 大鼠的 LC 中水平更高，PVN 中水平更低。总体而言，这些数据进一步验证了我们的远交特质焦虑大鼠：HAn 雄性表现出焦虑样行为、AMPH 过度敏感、更大的冲动性以及边缘和中脑 5-HT1A 和 α2 肾上腺素能受体蛋白水平的变化。
