Alterations in Reward Processing During Drug Abstinence

描述（由申请人提供）：我们最近发现依赖吗啡的大鼠在停药后2周和5周表现出学习能力下降和对食物奖励的偏好。我们还发现，在停药后的同一时间段内，动物对与吗啡相关的环境线索的偏好增加。这些地方条件反射范式提供了一个简单的模型，在阿片戒断期间发生的奖励加工失调和烦躁不安。这种失调通常被认为有助于提高对药物和药物相关刺激的偏好或寻求。我们的目标是确定这种奖励处理长期变化背后的神经变化。初步数据显示，伏隔核外壳、下丘脑外侧和杏仁核基底外侧的神经元对食物或吗啡条件刺激的反应与偏好表达的数量成正比。我们假设，在这些调节腹侧被盖区（VTA）多巴胺神经元的区域，神经功能的改变与享乐价值的相关转移密切相关。我们进一步提出，在长时间戒断期间，这些VTA传入事件中的蛋白激酶A功能发生了改变，导致可塑性受损。中皮质边缘多巴胺系统中神经可塑性的变化被认为是奖励处理长期变化的基础。为了验证这些假设，我们提出了一系列的行为和解剖学研究。总之，这些研究将确定慢性药物暴露后奖赏加工和享乐价值改变的神经基质，这可能是长期戒断期间复发的关键。

DESCRIPTION (provided by applicant): We recently found that rats made dependent on morphine show decreased learning and preference for food reward at both two and five weeks post-withdrawal. We also found that animals show increased preference for morphine-associated environmental cues during these same time periods after withdrawal. These place-conditioning paradigms provide a simple model of the dysregulation of reward processing and dysphoria that occurs during opiate abstinence. This dysregulation is generally believed to contribute to elevated preference or seeking for drugs and drug-related stimuli. Our goal is to identify the neural changes that underlie this long-term alteration of reward processing. Preliminary data revealed that neurons in the nucleus accumbens shell, lateral hypothalamus and basolateral amygdala alter their responsiveness to food- or morphine-conditioned stimuli in proportion to the amount of preference expressed. We hypothesize that changed neural function in these areas that regulate ventral tegmental area (VTA) dopamine neurons is critically involved in the associated shift in hedonic values. We further propose that protein kinase A function is altered in these VTA afferents during protracted withdrawal, resulting in compromised plasticity. This change in neural plasticity in the mesocorticolimbic dopamine system is proposed to underlie long term alterations in reward processing. A coordinate set of behavioral and anatomical studies is proposed to test these hypotheses. Together, these studies will identify neural substrates for altered reward processing and hedonic values following chronic drug exposure that may be critical in relapse during long-term abstinence.