Spontaneously Hypertensive Rat substrains show differences in model traits for addiction risk and cocaine self-administration: Implications for a novel rat reduced complexity cross.
Spontaneously Hypertensive Rat substrains show differences in model traits for addiction risk and cocaine self-administration: Implications for a novel rat reduced complexity cross.
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DOI：
10.1016/j.bbr.2021.113406
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发表时间：
2021-08-06
影响因子：
2.7
通讯作者：
Bryant CD
中科院分区：
文献类型：
--
作者：
Kantak KM;Stots C;Mathieson E;Bryant CD
在近亲交配的啮齿动物亚系之间进行F2杂交的正向遗传作图-被称为降低复杂性杂交(RCC)-是一种相对较新的策略，可以加快药物成瘾等复杂性状的基因发现步伐。到目前为止，RCC是在小鼠身上产生的，但大鼠被认为是进行成瘾遗传学研究的最佳选择。根据过去的文献，一个近交系自发性高血压大鼠亚系SHR/NCr1被预测表现出明显的行为特征，因为它与另一个亚系SHR/nhsd的可卡因自我给药特征有关。直接亚应变比较是实施碾压混凝土之前必要的第一步。我们使用纵向受试者内设计评估了可卡因成瘾风险和可卡因自我给药行为的模型特征。SHR/NCr1比SHR/NHSD的冲动性和强迫性特征更强，对蔗糖奖励的反应性，对可卡因的急性精神刺激效应的敏感性，以及在固定比例和串联可卡因自我给药程序下研究的可卡因使用。强迫性行为与可卡因的急性精神刺激作用有关，而可卡因的急性精神刺激作用又与在串联时间表下服用可卡因有关。强迫性行为也是可卡因寻求反应的最佳预测因素。遗传力估计表明，上述表型的22%-40%的变异可以用加性遗传因素解释，这为SHR/NCr1和SHR/nhsd的F2杂交提供了足够的遗传变异。这些结果为在SHR亚株中使用RCC方法来发现与可卡因使用障碍相关的候选基因和变异提供了令人信服的支持。
Forward genetic mapping of F2 crosses between closely related substrains of inbred rodents - referred to as a reduced complexity cross (RCC) - is a relatively new strategy for accelerating the pace of gene discovery for complex traits, such as drug addiction. RCCs to date were generated in mice, but rats are thought to be optimal for addiction genetic studies. Based on past literature, one inbred Spontaneously Hypertensive Rat substrain, SHR/NCrl, is predicted to exhibit a distinct behavioral profile as it relates to cocaine self-administration traits relative to another substrain, SHR/NHsd. Direct substrain comparisons are a necessary first step before implementing an RCC. We evaluated model traits for cocaine addiction risk and cocaine self-administration behaviors using a longitudinal within-subjects design. Impulsive-like and compulsive-like traits were greater in SHR/NCrl than SHR/NHsd, as were reactivity to sucrose reward, sensitivity to acute psychostimulant effects of cocaine, and cocaine use studied under fixed-ratio and tandem schedules of cocaine self-administration. Compulsive-like behavior correlated with the acute psychostimulant effects of cocaine, which in turn correlated with cocaine taking under the tandem schedule. Compulsive-like behavior also was the best predictor of cocaine seeking responses. Heritability estimates indicated that 22%-40% of the variances for the above phenotypes can be explained by additive genetic factors, providing sufficient genetic variance to conduct genetic mapping in F2 crosses of SHR/NCrl and SHR/NHsd. These results provide compelling support for using an RCC approach in SHR substrains to uncover candidate genes and variants that are of relevance to cocaine use disorders.
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