Alterations in Reward Processing During Drug Abstinence

描述(申请人提供)：我们最近发现，依赖吗啡的大鼠在戒断后两周和五周表现出学习能力和对食物奖励的偏好下降。我们还发现，在戒断后的相同时间段，动物对与吗啡相关的环境线索表现出更多的偏好。这些地方条件作用范式提供了一个简单的模型，说明在阿片类药物戒断期间发生的奖赏加工和烦躁不安的失调。这种失调通常被认为是导致偏爱或寻求药物和药物相关刺激的原因之一。我们的目标是确定这种奖励处理的长期变化背后的神经变化。初步数据显示，伏隔核壳核、下丘脑外侧核和杏仁基底外侧核的神经元对食物或吗啡条件刺激的反应与表达的偏爱程度成比例。我们假设，调节腹侧被盖区(VTA)多巴胺神经元的这些区域神经功能的改变与相关享乐值的变化密切相关。我们进一步提出，在长时间的戒断过程中，这些VTA传入神经元中的蛋白激酶A功能发生了变化，导致可塑性受损。这种中皮质边缘多巴胺系统神经可塑性的变化被认为是奖赏处理的长期变化的基础。一组协调的行为和解剖学研究被提出来检验这些假说。总之，这些研究将确定慢性药物暴露后奖赏处理和享乐性价值观改变的神经底物，这可能是长期戒毒期间复发的关键。

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.