Dickson Price E, Datta Udita, Wilcox Troy D, Auth Ashley A, Ball Robyn L, Dunn Matt, Fisher Heidi S, Klein Alyssa, Leonardo Michael R, Roy Tyler A, Saul Michael C, Bubier Jason A, Gagnon Leona H, Philip Vivek M, Tarantino Lisa M, Jentsch James D, Chesler Elissa J
Mammalian Genetics, The Jackson Laboratory, Bar Harbor, ME, USA.
Center for Systems Neurogenetics of Addiction, The Jackson Laboratory, Bar Harbor, ME, USA.
Psychopharmacology (Berl). 2025 Sep 15. doi: 10.1007/s00213-025-06904-w.
Genetic and other predisposing factors can influence the progression from initiation of drug intake to compulsive substance use through distinct biobehavioral processes. Operant cocaine self-administration studies in laboratory mice offer a powerful method to dissect the biology of this progression from initiation, dose-response, extinction, and cued reinstatement in a controlled, tractable system. However, many such studies encompass limited genetic diversity and rarely examine self-administration behaviors beyond the acquisition stage. Here, we study three high-diversity mouse populations - 50 strains from the Collaborative Cross (CC) reference panel, a large sample of Diversity Outbred (J: DO) population and their eight founder strains - to characterize the varied phenotypic manifestation of behaviors across multiple phases of cocaine intravenous self-administration (IVSA) in both sexes. We observed distinct strain differences among the founders and CC strains in all phases of self-administration, with heritability estimates ranging from 0 to 0.585 and many CC and J: DO phenotypic values exceeding the range of founders including the C57BL/6J strain. Sex differences were common across behaviors, some manifesting as main effects, others as strain interactions. Finally, by adopting a multi-stage design, we identified extreme strains for various cocaine intake and response traits. Together, these findings demonstrate the utility of extended self-administration protocols in high-diversity mouse populations and establish feasibility for their use in the discovery and characterization of biological mechanisms of substance use traits and for preclinical studies in relevant, complex mouse models.
遗传因素和其他诱发因素可通过不同的生物行为过程，影响从开始摄入药物到强迫性物质使用的进展。实验室小鼠的操作性可卡因自我给药研究提供了一种强大的方法，可在一个可控、易处理的系统中剖析这一进展过程中的生物学机制，包括起始、剂量反应、消退和线索复吸等方面。然而，许多此类研究的遗传多样性有限，并且很少在获取阶段之外研究自我给药行为。在这里，我们研究了三个具有高遗传多样性的小鼠群体——协作杂交（CC）参考面板中的50个品系、大量多样性远交（J:DO）群体样本及其八个创始品系——以表征两性在可卡因静脉自我给药（IVSA）多个阶段行为的不同表型表现。我们观察到创始品系和CC品系在自我给药的所有阶段均存在明显的品系差异，遗传力估计值范围为0至0.585，许多CC和J:DO品系的表型值超出了包括C57BL/6J品系在内的创始品系的范围。行为中的性别差异很常见，有些表现为主效应，有些表现为品系间相互作用。最后，通过采用多阶段设计，我们确定了各种可卡因摄入和反应性状的极端品系。总之，这些发现证明了扩展自我给药方案在高遗传多样性小鼠群体中的实用性，并确立了其在发现和表征物质使用性状的生物学机制以及在相关复杂小鼠模型的临床前研究中应用的可行性。
