Association of novelty-related behaviors and intravenous cocaine self-administration in Diversity Outbred mice
Association of novelty-related behaviors and intravenous cocaine self-administration in Diversity Outbred mice
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DOI：
10.1007/s00213-014-3737-5
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发表时间：
2015-03-01
影响因子：
3.4
通讯作者：
Chesler, Elissa J.
中科院分区：
文献类型：
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作者：
Dickson, Price E.;Ndukum, Juliet;Chesler, Elissa J.
对新奇事物的偏好和反应与可卡因和其他药物成瘾密切相关。然而，这些现象背后的遗传变异和分子机制仍然很大程度上未知。尽管在大鼠中观察到了新奇和成瘾相关特征之间的关系，但对小鼠的研究未能证明这种关联。包括 Diversity Outbred (DO) 小鼠在内的新的、遗传多样性、高精度的小鼠群体提供了评估扩大范围的行为变异的机会，从而能够检测小鼠中新奇和成瘾相关特征的关联。为了检查新奇和成瘾相关特征之间的关系，对雄性 (n = 51) 和雌性 (n = 47) DO 小鼠进行了旷场探索、孔板探索和新奇偏好测试，然后进行静脉注射可卡因自我给药 (IVSA; 10固定比例 1 的 2 小时疗程和渐进比例的 6 小时疗程）。我们观察到 DO 小鼠中可卡因 IVSA 的高度变化，其中 43% 达到了常规获取标准，57% 未达到常规获取标准。作为一个群体，没有达到这些标准的小鼠仍然表现出明显的杠杆歧视。经历导管闭塞或其他技术问题的小鼠 (n = 17) 被排除在分析之外。新奇相关行为与可卡因 IVSA 呈正相关。对新颖性和成瘾相关性状之间关联的多变量分析揭示了很大程度的共同方差（45％）。DO小鼠中可卡因IVSA和新颖性相关表型之间的协变表明这种关系适合于基因解剖。 DO 的高遗传精度和表型多样性可能有助于发现以前无法检测到的成瘾性疾病易感性机制。
The preference for and reaction to novelty are strongly associated with addiction to cocaine and other drugs. However, the genetic variants and molecular mechanisms underlying these phenomena remain largely unknown. Although the relationship between novelty- and addiction-related traits has been observed in rats, studies in mice have failed to demonstrate this association. New, genetically diverse, high-precision mouse populations including Diversity Outbred (DO) mice provide an opportunity to assess an expanded range of behavioral variation enabling detection of associations of novelty- and addiction-related traits in mice.To examine the relationship between novelty- and addiction-related traits, male (n = 51) and female (n = 47) DO mice were tested on open field exploration, hole board exploration, and novelty preference followed by intravenous cocaine self-administration (IVSA; ten 2-h sessions of fixed ratio 1 and one 6-h session of progressive ratio).We observed high variation of cocaine IVSA in DO mice with 43 % reaching and 57 % not reaching conventional acquisition criteria. As a group, mice that did not reach these criteria still demonstrated significant lever discrimination. Mice experiencing catheter occlusion or other technical issues (n = 17) were excluded from the analysis. Novelty-related behaviors were positively associated with cocaine IVSA. Multivariate analysis of associations among novelty- and addiction-related traits revealed a large degree of shared variance (45 %).Covariation among cocaine IVSA and novelty-related phenotypes in DO mice indicates that this relationship is amenable to genetic dissection. The high genetic precision and phenotypic diversity in the DO may facilitate discovery of previously undetectable mechanisms underlying predisposition to develop addiction disorders.