Alterations in Reward Processing During Drug Abstinence

描述（由申请人提供）：我们最近发现，依赖吗啡的大鼠在戒断后两周和五周表现出学习能力下降和对食物奖励的偏好。我们还发现，在戒断后的同一时间段内，动物对吗啡相关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，在阿片类药物戒断过程中发生的奖励处理和烦躁不安的失调。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。我们的目标是确定奖励处理长期改变的神经变化。初步的数据显示，在核壳，外侧下丘脑和基底外侧杏仁核的神经元改变他们的反应食物或吗啡条件刺激的数量的偏好表示成比例。我们假设，在这些地区，调节腹侧被盖区（VTA）多巴胺神经元的神经功能的变化是至关重要的参与相关的享乐价值观的转变。我们进一步提出，蛋白激酶A的功能被改变，在这些VTA传入在长期撤退，导致可塑性受损。中皮质边缘多巴胺系统神经可塑性的这种变化被认为是奖励过程长期改变的基础。提出了一套协调的行为和解剖学研究来验证这些假设。总之，这些研究将确定神经基板改变奖励处理和享乐价值观后，慢性药物暴露，可能是至关重要的复发在长期禁欲。

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.