Plasticity of excitability in ventral subiculum after high cocaine intake

描述(申请人提供)：一些人能够随意地尝试毒品，如可卡因，而另一些人则增加药物摄入量，并强制寻求药物，以至于上瘾。像吸毒者一样，自我注射可卡因的动物会调整自己的摄入量，以维持大脑中可卡因和多巴胺的最佳水平，这最终决定了调节行为的神经回路中的神经活动模式。确定负责控制药物摄取和寻找反馈的可塑性的特定神经机制是理解成瘾的基础。长时间(6小时)获得可卡因自我给药的动物模型再现了吸毒者在戒毒期间经常看到的高水平的药物摄取和增强的可卡因寻找。到目前为止，还没有体外研究测量与长时间使用自愿可卡因有关的神经生理适应，也没有任何研究检验灭绝学习逆转神经生理适应的可能性。赛尔夫和他的同事(2003)证明了消退学习能够逆转可卡因自我给药引起的几个分子变化，并提出了消退在成瘾治疗中的作用。不幸的是，几乎所有检测突触或内在可塑性的研究都使用了非偶然的、实验者递送的药物，这不允许发生灭绝学习。虽然非偶然给药在诱导行为可塑性方面有效，但与敏化一样，它缺乏意志和动机成分，以及奖赏回路中对突触可塑性至关重要的大脑区域的间歇性短暂激活。理想情况下，一个值得研究的候选脑区应该具备以下标准：1)大脑奖赏回路内的大量神经支配；2)对奖赏刺激和条件性刺激或与之相关的环境的神经反应；3)多巴胺和可卡因对神经元活动的调制；3)与奖赏相关记忆的形成或储存；4)调节多巴胺神经元活动或奖赏回路中的水平；5)双向调节已消失的反应(即神经元激活触发和抑制减少恢复)。很少有大脑区域符合所有这些标准，然而，腹侧下丘--海马体的主要输出结构和与多巴胺系统的接口--就是这样一个结构。我们过去的体外实验表明腹侧下丘脑对反复精神刺激诱导的可塑性很敏感。本研究拟研究腹侧海马CA1区突触和内源性兴奋性及多巴胺调节与可卡因自身给药的获得、维持和戒断/消失相关的兴奋性。我们将使用最先进的通道平面多电极阵列场电位记录和全细胞膜片钳记录相结合的方法，对接受过短期或长期可卡因自我给药训练的大鼠进行记录。成瘾的两个特点是失去可控的药物摄入和相关的高复发风险。确定控制药物摄取和寻找反馈的大脑区域和特定的神经机制是理解加法的基础。我们的目标是使用或有意志药物摄入的可卡因自我给药行为模型，使我们能够将可卡因的摄取和戒毒与神经生理兴奋性的详细测量相关联，以更好地理解与成瘾有关的记忆相关的神经可塑性。

DESCRIPTION (provided by applicant): Some people are capable of experimenting casually with drugs, like cocaine, while others escalate their drug intake and seek drugs compulsively to the point of addiction. Like addicts, animals self-administering cocaine adjust their intake to maintain optimal brain cocaine and dopamine levels that ultimately determine the pattern of neural activity in circuits that regulate the behavior. Identifying the specific neuronal mechanisms responsible for the plasticity that controls the feedback on drug intake and drug-seeking is fundamental to understanding addiction. The prolonged (6 hr) access animal model of cocaine self- administration reproduces the high levels of drug intake and enhanced cocaine-seeking during periods of drug abstinence often seen in drug addicts. To date, no in vitro studies have measured the neurophysiological adaptations associated with prolonged access volitional cocaine administration, nor have any studies examined the potential for extinction learning to reverse the neurophysiological adaptations. Self and colleagues (2003) have demonstrated that extinction learning is capable of reversing several molecular changes induced by cocaine self- administration and have proposed a role for extinction in addiction therapy. Unfortunately, almost all studies examining synaptic or intrinsic plasticity have used noncontingent, experimenter delivered drug, which does not allow extinction learning to occur. While effective at inducing behavioral plasticity, like sensitization, noncontingent drug delivery lacks the volitional and motivational components as well as the intermittent temporal activation of brain regions in the reward circuitry important for synaptic plasticity. Ideally, a candidate brain region worth investigating for a role in the plasticity associated with escalation or incubation of cocaine craving would have the following criteria; 1) Substantial innervation within the brain reward circuitry; 2) Neural responses to rewarding stimuli and conditioned stimuli or contexts associated with them; 3) Modulation of neuronal activity by dopamine and cocaine; 3) A role in the formation or storage of reward-related memory; 4) Regulation of dopamine neuronal activity or levels in the reward circuit; 5) Bidirectional regulation of reinstatement of extinguished responding (i.e. neuronal activation triggers and inhibition decreases reinstatement). Few brain regions meet all of these criteria, however, the ventral subiculum -- the major hippocampal output structure and interface to the dopamine system -- is one such structure that does. Our past in vitro experiments have shown the ventral subiculum to be susceptible to repeated psychostimulant-induced plasticity. This study proposes to study synaptic and intrinsic excitability and dopamine modulation of ventral hippocampal CA1-subicular excitability that is associated with acquisition, maintenance, and withdrawal/extinction of cocaine self administration. We will use a combination of state-of-the-art 64 channel planar multielectrode array field potential recording and whole-cell patch clamp recording in rats that have been trained for either short access or long access to cocaine self-administration. Two hallmark features of addiction are the loss of controlled drug intake and the associated high relapse risk. Identifying the brain regions and specific neuronal mechanisms that control the feedback on drug intake and drug-seeking is fundamental to understanding addition. Our goal is to use the cocaine self-administration behavioral model of contingent volitional drug intake to allow us to correlate cocaine intake and extinction of drug taking with detailed measures of neurophysiological excitability for the purposes of better understanding the neural plasticity associated with memory linked to addiction.