Department of Neurobiology and Anatomy, Drexel University College of Medicine, Philadelphia, PA, USA.
Department of Psychiatry, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA.
Neuropsychopharmacology. 2021 Sep;46(10):1757-1767. doi: 10.1038/s41386-021-01009-2. Epub 2021 May 5.
A major theme of addiction research has focused on the neural substrates of individual differences in the risk for addiction; however, little is known about how vulnerable populations differ from those that are relatively protected. Here, we prospectively measured dopamine (DA) neurotransmission prior to cocaine exposure to predict the onset and course of cocaine use. Using in vivo voltammetry, we first generated baseline profiles of DA release and uptake in the dorsomedial striatum (DMS) and nucleus accumbens of drug-naïve male rats prior to exposing them to cocaine using conditioned place preference (CPP) or operant self-administration. We found that the innate rate of DA uptake in the DMS strongly predicted motivation for cocaine and drug-primed reinstatement, but not CPP, responding when "price" was low, or extinction. We then assessed the impact of baseline variations in DA uptake on cocaine potency in the DMS using ex vivo voltammetry in naïve rats and in rats with DA transporter (DAT) knockdown. DA uptake in the DMS of naïve rats predicted the neurochemical response to cocaine, such that rats with innately faster rates of DA uptake demonstrated higher cocaine potency at the DAT and rats with DAT knockdown displayed reduced potency compared to controls. Together, these data demonstrate that inherent variability in DA uptake in the DMS predicts the behavioral response to cocaine, potentially by altering the apparent potency of cocaine.
成瘾研究的一个主要主题集中在个体对成瘾风险差异的神经基础上；然而，对于易受影响的人群与相对受保护的人群有何不同，我们知之甚少。在这里，我们前瞻性地测量了多巴胺（DA）神经递质在可卡因暴露前的释放和摄取，以预测可卡因使用的开始和过程。使用活体伏安法，我们首先在可卡因暴露之前，在药物-naïve 雄性大鼠的背内侧纹状体（DMS）和伏隔核中生成 DA 释放和摄取的基线图谱，使用条件位置偏好（CPP）或操作性自我给药来暴露它们。我们发现，DMS 中 DA 摄取的固有速率强烈预测了可卡因的动机和药物引发的复吸，但不能预测 CPP 反应的“价格”低时，或消退。然后，我们使用在体伏安法在 naïve 大鼠和 DA 转运蛋白（DAT）敲低大鼠中评估了 DMS 中 DA 摄取的基线变化对可卡因效力的影响。naïve 大鼠 DMS 中的 DA 摄取预测了对可卡因的神经化学反应，因此固有 DA 摄取速率较快的大鼠在 DAT 处表现出更高的可卡因效力，而 DAT 敲低的大鼠与对照相比表现出较低的效力。总之，这些数据表明，DMS 中 DA 摄取的固有可变性预测了对可卡因的行为反应，可能通过改变可卡因的表观效力来实现。
