Weber Sophia J, Kawa Alex B, Beutler Madelyn M, Kuhn Hayley M, Moutier Alana L, Westlake Jonathan G, Koyshman Lara M, Moreno Cloe D, Wunsch Amanda M, Wolf Marina E
Department of Behavioral Neuroscience, Oregon Health & Science University, Portland, OR, USA.
Neuropsychopharmacology. 2024 Dec;50(2):461-471. doi: 10.1038/s41386-024-01992-2. Epub 2024 Sep 19.
Relapse represents a consistent clinical problem for individuals with substance use disorder. In the incubation of craving model of persistent craving and relapse, cue-induced drug seeking progressively intensifies or "incubates" during the first weeks of abstinence from drug self-administration and then remains high for months. Previously, we and others have demonstrated that expression of incubated cocaine craving requires strengthening of excitatory synaptic transmission in the nucleus accumbens core (NAcc). However, despite the importance of dopaminergic signaling in the NAcc for motivated behavior, little is known about the role that dopamine (DA) plays in the incubation of cocaine craving. Here we used fiber photometry to measure DA transients in the NAcc of male and female rats during cue-induced seeking tests conducted in early abstinence from cocaine self-administration, prior to incubation, and late abstinence, after incubation of craving has plateaued. We observed DA transients time-locked to cue-induced responding but their magnitude did not differ significantly when measured during early versus late abstinence seeking tests. Next, we tested for a functional role of these DA transients by injecting DA receptor antagonists into the NAcc just before the cue-induced seeking test. Blockade of either D1 or D2 DA receptors reduced cue-induced cocaine seeking after but not before incubation. We found no main effect of sex or significant interaction of sex with other factors in our experiments. These results suggest that DA contributes to incubated cocaine seeking but the emergence of this role reflects changes in postsynaptic responsiveness to DA rather than presynaptic alterations.
复发是物质使用障碍患者持续存在的临床问题。在持续渴望和复发的渴望潜伏期模型中，线索诱导的药物寻求行为在停止自我给药后的头几周内逐渐增强或“潜伏期延长”，然后在数月内保持高水平。此前，我们和其他人已经证明，潜伏期延长的可卡因渴望的表达需要伏隔核核心（NAcc）中兴奋性突触传递的增强。然而，尽管NAcc中的多巴胺能信号传导对动机行为很重要，但关于多巴胺（DA）在可卡因渴望潜伏期延长中所起的作用却知之甚少。在这里，我们使用光纤光度法测量雄性和雌性大鼠在停止可卡因自我给药后的早期（潜伏期之前）和晚期（渴望潜伏期延长达到平稳期之后）进行线索诱导寻求测试期间NAcc中的DA瞬变。我们观察到DA瞬变与线索诱导的反应时间锁定，但在早期与晚期禁欲寻求测试期间测量时，其幅度没有显著差异。接下来，我们通过在线索诱导寻求测试前向NAcc注射DA受体拮抗剂来测试这些DA瞬变的功能作用。阻断D1或D2 DA受体会降低潜伏期延长后但不是潜伏期延长前的线索诱导的可卡因寻求行为。我们在实验中没有发现性别主效应或性别与其他因素的显著交互作用。这些结果表明，DA有助于潜伏期延长的可卡因寻求行为，但这种作用的出现反映了突触后对DA反应性的变化，而不是突触前的改变。
