Department of Pharmacology and Neuroscience, University of North Texas Health Science Center at Fort Worth, 3500 Camp Bowie Blvd, Fort Worth, TX, 76107, USA.
Psychopharmacology (Berl). 2022 Aug;239(8):2593-2603. doi: 10.1007/s00213-022-06130-8. Epub 2022 Apr 28.
Drug-seeking behavior occurs more readily in some individuals than others. This phenomenon is considered in studies of drug self-administration in which high drug-seeking/taking individuals can be identified. In contrast, studies of conditioned place preference (CPP) often involve a random sample of drug-naïve rodents that includes phenotypes not considered relevant to addiction. The main objective of the current studies was to determine if a priori identification of different conditioning phenotypes could improve the validity and sensitivity of CPP expression as a preclinical test for vulnerability to addiction.
Analysis of cocaine place conditioning data from 443 Swiss-Webster mice revealed a trimodal distribution with peaks corresponding to means of k = 3 clusters. The cluster means occurred at high, low, or negative preference scores, the latter suggesting a phenotype acquiring conditioned place aversion (CPA). The same clusters were identified in mice conditioned with methamphetamine, MDPV, or amphetamine, and these clusters remained stable and reliable during three additional expression tests spaced at 24 h. A meta-analysis of effect sizes obtained from CPP literature revealed a positively skewed distribution affected by sample size, consistent with the existence of a CPA phenotype within the populations tested. A dopamine receptor antagonist, flupentixol, blocked cocaine CPP expression in a group containing all phenotypes, but sensitivity improved markedly when CPA phenotypes were excluded from the dataset.
These studies suggest that taking phenotype into consideration when designing place conditioning studies will improve their application as a preclinical tool in addiction biology and drug discovery.
药物寻求行为在某些个体中比在其他个体中更容易发生。这种现象在药物自我给药研究中被考虑，其中可以识别出高药物寻求/摄取个体。相比之下，条件位置偏好（CPP）的研究通常涉及药物-naive 啮齿动物的随机样本，其中包括与成瘾无关的表型。当前研究的主要目的是确定是否可以预先确定不同的条件化表型，从而提高 CPP 表达作为成瘾易感性的临床前测试的有效性和敏感性。
对 443 只瑞士-韦伯斯特小鼠可卡因位置条件作用数据的分析显示，存在一个三模态分布，峰值对应于 k=3 个聚类的均值。聚类均值出现在高、低或负偏好评分处，后者表明出现了获得条件位置厌恶（CPA）的表型。在接受甲基苯丙胺、MDPV 或安非他命条件作用的小鼠中也发现了相同的聚类，并且在 24 小时的三个额外表达测试期间，这些聚类保持稳定和可靠。对 CPP 文献中获得的效应大小的荟萃分析显示，分布存在正偏态，受样本量影响，与所测试人群中存在 CPA 表型一致。多巴胺受体拮抗剂氟奋乃静阻断了可卡因 CPP 的表达，在包含所有表型的一组中，但当从数据集中排除 CPA 表型时，敏感性明显提高。
这些研究表明，在设计位置条件作用研究时考虑表型，将提高它们在成瘾生物学和药物发现中的临床前工具应用。
