CUE CONTROLLED DRUG TAKING--ACCUMBAL NEUROPHYSIOLOGY

描述：(申请人摘要) 毒瘾是一种以强迫性药物为特征的慢性复发性疾病。 寻找。这种疾病会严重损害个人的健康，并具有 给公众带来各种负面的健康和经济后果。这个 治疗成瘾的有效疗法的发展和 因此，预防复发非常重要。的动物和人体研究 成瘾已经证明，这种疾病具有重要的神经生物学意义。 决定因素。成瘾的激励动机理论认为，中心 对这些神经生物学决定因素是成瘾药物对 激励激励大脑的动力回路。据推测，在 正常情况此电路由自然的主要激励因素激活 比如食物。与神经激活相关的情景刺激 条件性激励刺激属性，因此，方向性影响 行为过激。有人提出使人上瘾的药物激活相同的电路， 尽管它的疗效要好得多。因此，与毒品有关的 情景刺激产生不成比例的强烈条件性激励 属性，并最终发挥主导作用，相对于其他刺激， 在组织行为方面。与这一假设一致的是，与药物相关的刺激 据报道，吸毒者会引起无法抗拒的寻求毒品的冲动，而且 被认为是导致吸毒行为复发的主要因素。 中脑边缘多巴胺靶神经元，包括核内神经元 伏隔(NAcc)，被认为是 与强迫性药物有关的药物改变的动力回路 寻求，尤其是受与毒品有关的条件性刺激控制的。这个 本提案的目的是检验以下几个基本预测 这种“累积式激励动机”假说。这些预测包括 跟在后面。首先，单个NAcc神经元将显示出规则的变化 当受试者1)接触相关条件药物时的射击率 激励刺激和/或2)从事受控制的毒品行为 那些刺激。第二，NAcc神经元，包括那些对药物相关的反应 刺激物，会对用药敏感。拟议的研究将 使用慢性活体细胞外记录技术记录活动 自由活动大鼠单个NAcc核壳神经元的研究 两种行为过程中的寻药行为：1)二级行为 静脉注射可卡因自我给药和2)线索恢复 会话。在这些会议期间采用的程序涉及 先前与自我给药配对的外部感觉刺激的呈现 毒品，并另外产生明显的寻毒行为 由毒品相关的刺激控制。预测的存在或不存在 因此，这些治疗过程中的神经反应将提供重要信息 关于蓄积激励动机假说的有效性。

DESCRIPTION: (Applicant's Abstract) Drug addiction is a chronic relapse disorder characterized by compulsive drug seeking. The disorder can damage severely the health of the individual and has a variety of negative health and financial consequences for the public. The development of effective therapies for the treatment of addiction and the prevention of relapse is thus of great importance. Animal and human studies of addiction have demonstrated that the disorder has important neurobiological determinants. Incentive Motivation theories of addiction propose that central to those neurobiological determinants are actions of addictive drugs on incentive motivation circuitry of the brain. It is hypothesized that under normal conditions this circuitry is activated by natural primary incentives such as food. Situational stimuli associated with the neural activation accrue conditioned incentive stimulus properties and, therefore, directional influence over behavior. It is proposed that addictive drugs activate the same circuitry, although with significantly greater efficacy. As a consequence, drug-associated situational stimuli accrue disproportionately strong conditioned incentive properties and eventually exert a predominant role, relative to other stimuli, in organizing behavior. Consistent with this hypothesis, drug-related stimuli are reported by addicts to evoke an irresistible urge to seek drug and are considered major factors in precipitating relapse to drug-addicted behavior. Mesolimbic dopamine target neurons, including neurons within the nucleus accumbens (NAcc), are hypothesized to be important components of the drug-altered motivational circuitry that contributes to compulsive drug seeking, particularly that controlled by conditioned drug-related stimuli. The aims of the present proposal are to test several fundamental predictions of this "accumbal incentive motivation" hypothesis. These predictions include the following. First, individual NAcc neurons will exhibit regular changes in firing rate when a subject either 1) is exposed to conditioned drug associated incentive stimuli and/or 2) is engaged in drug-seeking behavior controlled by those stimuli. Second, NAcc neurons, including those responsive to drug-related stimuli, will be sensitive to drug administration. The proposed studies will use chronic in vivo extracellular recording techniques to record the activity of single NAcc core and shell neurons of freely-moving rats engaged in drug-seeking behavior during each of two behavioral sessions: 1) second-order intravenous cocaine self-administration sessions and 2) cue reinstatement sessions. The procedures employed during these sessions involve the presentation of exteroceptive stimuli previously paired with self-administered drug and additionally engender drug-seeking behavior that is demonstrably controlled by drug-associated stimuli. The presence or absence of the predicted neural responses during those sessions will thus provide important information regarding the validity of the accumbal incentive motivation hypothesis.