Cocaine use disorder is a significant public health issue without an effective pharmacological treatment. Successful treatments are hindered in part by an incomplete understanding of the molecular mechanisms that underlie long-lasting maladaptive plasticity and addiction-like behaviors. Here, we leverage a large RNA sequencing dataset to generate gene coexpression networks across six interconnected regions of the brain's reward circuitry from mice that underwent saline or cocaine self-administration. We identify phosphodiesterase 1b (Pde1b), a Ca²⁺/calmodulin-dependent enzyme that increases cAMP and cGMP hydrolysis, as a central hub gene within a nucleus accumbens (NAc) gene module that was bioinformatically associated with addiction-like behavior. Chronic cocaine exposure increases Pde1b expression in NAc D2 medium spiny neurons (MSNs) in male but not female mice. Viral-mediated Pde1b overexpression in NAc reduces cocaine self-administration in female rats but increases seeking in both sexes. In female mice, overexpressing Pde1b in D1 MSNs attenuates the locomotor response to cocaine, with the opposite effect in D2 MSNs. Overexpressing Pde1b in D1/D2 MSNs had no effect on the locomotor response to cocaine in male mice. At the electrophysiological level, Pde1b overexpression reduces sEPSC frequency in D1 MSNs and regulates the excitability of NAc MSNs. Lastly, Pde1b overexpression significantly reduced the number of differentially expressed genes (DEGs) in NAc following chronic cocaine, with discordant effects on gene transcription between sexes. Together, we identify novel gene modules across the brain's reward circuitry associated with addiction-like behavior and explore the role of Pde1b in regulating the molecular, cellular, and behavioral responses to cocaine.

可卡因使用障碍是一个重大的公共卫生问题，没有有效的药物治疗。成功的治疗在一定程度上受到对长期不良适应可塑性和成瘾行为背后分子机制的不完全理解的阻碍。在这里，我们利用大型 RNA 测序数据集，在接受盐水或可卡因自我给药的小鼠大脑奖励回路的六个互连区域中生成基因共表达网络。我们确定磷酸二酯酶 1b (Pde1b) 是一种 Ca ²⁺ /钙调蛋白依赖性酶，可增加 cAMP 和 cGMP 水解，作为伏隔核 (NAc) 基因模块内的中心枢纽基因，该基因模块在生物信息学上与成瘾相关 -喜欢的行为。长期接触可卡因会增加雄性小鼠 NAc D2 中型多棘神经元 (MSN) 中 Pde1b 的表达，但雌性小鼠则不会。 NAc 中病毒介导的 Pde1b 过表达会减少雌性大鼠的可卡因自我给药，但会增加雌性大鼠的寻找可卡因的行为。在雌性小鼠中，D1 MSN 中 Pde1b 的过度表达会减弱对可卡因的运动反应，而在 D2 MSN 中则产生相反的效果。在 D1/D2 MSN 中过表达 Pde1b 对雄性小鼠对可卡因的运动反应没有影响。在电生理水平上，Pde1b 过表达会降低 D1 MSN 中的 sEPSC 频率，并调节 NAc MSN 的兴奋性。最后，Pde1b 过度表达显着减少了慢性可卡因后 NAc 中差异表达基因 (DEG) 的数量，对性别之间的基因转录产生不一致的影响。 我们共同确定了大脑奖励回路中与成瘾样行为相关的新基因模块，并探索了 Pde1b 在调节可卡因的分子、细胞和行为反应中的作用。