Comparison of gene expression in the nucleus accumbens of rats expressing or not the conditioned place preference to cocaine [CPPE, nCPPE, Saline]

Substance use disorder emerges in a small proportion of drug users and has the characteristics of a chronic relapsing pathology. The objective of our study was to demonstrate and characterize the variability in the expression of the reinforcing effects of cocaine in the conditioned place preference (CPP) paradigm. An unbiased cocaine-CPP paradigm in Sprague-Dawley rats with an extinction period of 12 days and reinstatement was conducted. We developed a statistical model to distinguish rats that express or do not express cocaine-induced place preference. Two groups of rats were identified: rats that did express reinforcing effects (CPP expression (CPPE), score > 102 s) and rats that did not (no CPP expression (nCPPE), score between −85 and 59 s). These two groups did not show significant differences in a battery of behavioral tests. To identify differentially expressed genes in the CPPE and nCPPE groups, we performed a whole-transcriptome RNA-sequencing analysis in the nucleus accumbens (Nac) 24 h after the CPP test. Four immediate early genes (Fos, Egr2, Nr4a1 and Zbtb37) were differentially expressed in the Nac of CPPE rats after CPP memory retrieval. Variability in cocaine-induced place preference persisted in the CPPE and nCPPE groups after the extinction and reinstatement phases. Transcriptomic differences observed after reinstatement were distinct from those observed immediately after CPP memory retrieval. These new findings provide insights into the identification of mechanisms underlying interindividual variability in the response to cocaine's reinforcing effects. Cocaine CPP was performed in 8-week-old Sprague-Dawley rats and the nucleus accumbens transcriptomes of CPPE, nCPPE and Saline rats were compared.

物质使用障碍（Substance use disorder）仅在少数药物使用者中出现，具有慢性复发性病理特征。本研究旨在验证并解析可卡因在条件性位置偏爱（conditioned place preference, CPP）范式中强化效应的表达差异。研究采用无偏倚可卡因-CPP范式，对斯普拉-道来大鼠开展了为期12天的消退训练，并实施了复燃实验。我们开发了一套统计模型，以区分表达与不表达可卡因诱导性位置偏爱的大鼠。最终鉴定出两组大鼠：表现出强化效应的CPP表达组（CPP expression, CPPE，得分>102秒），以及未表现出该效应的无CPP表达组（no CPP expression, nCPPE，得分介于-85至59秒之间）。两组大鼠在一系列行为学测试中均未呈现显著差异。为鉴定CPPE与nCPPE组间的差异表达基因，我们在CPP测试结束24小时后，对伏隔核（nucleus accumbens, Nac）开展了全转录组RNA测序分析。在CPP记忆提取后，CPPE组大鼠伏隔核内的4种即刻早期基因（Fos、Egr2、Nr4a1及Zbtb37）呈现差异表达。在消退与复燃阶段后，CPPE与nCPPE组大鼠的可卡因诱导性位置偏爱差异仍持续存在。复燃后观测到的转录组差异，与CPP记忆提取后即刻观测到的转录组差异存在显著区别。本研究的新发现为解析个体间对可卡因强化效应应答差异的潜在机制提供了新视角。本实验以8周龄的斯普拉-道来大鼠为对象开展可卡因CPP实验，并对CPPE组、nCPPE组及生理盐水组大鼠的伏隔核转录组进行了比较分析。