Dickson Price E, Ndukum Juliet, Wilcox Troy, Clark James, Roy Brittany, Zhang Lifeng, Li Yun, Lin Da-Ting, Chesler Elissa J
The Jackson Laboratory, 600 Main Street, Bar Harbor, ME, 04609, USA.
Psychopharmacology (Berl). 2015 Mar;232(6):1011-24. doi: 10.1007/s00213-014-3737-5. Epub 2014 Sep 20.
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.
对新奇事物的偏好和反应与可卡因及其他药物成瘾密切相关。然而，这些现象背后的基因变异和分子机制仍 largely unknown。尽管在大鼠中已观察到新奇事物与成瘾相关特征之间的关系，但在小鼠中的研究未能证实这种关联。包括多样性远交（DO）小鼠在内的新的、具有遗传多样性的高精度小鼠群体提供了一个机会，可评估行为变异的更广泛范围，从而能够检测小鼠中新奇事物与成瘾相关特征的关联。
为了研究新奇事物与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、洞板探索和新奇偏好测试，随后进行静脉注射可卡因自我给药（IVSA；十次2小时的固定比率1训练和一次6小时的累进比率训练）。
我们观察到DO小鼠中可卡因IVSA存在高度变异，43%达到且57%未达到传统的习得标准。作为一个群体，未达到这些标准的小鼠仍表现出显著的杠杆辨别能力。经历导管阻塞或其他技术问题的小鼠（n = 17）被排除在分析之外。与新奇事物相关的行为与可卡因IVSA呈正相关。对新奇事物与成瘾相关特征之间的关联进行多变量分析发现，存在很大程度的共同方差（45%）。
DO小鼠中可卡因IVSA与新奇事物相关表型之间的共变表明，这种关系适合进行基因剖析。DO小鼠的高遗传精度和表型多样性可能有助于发现先前未检测到的成瘾性疾病易感性潜在机制。
