Plasticity of excitability in ventral subiculum after high cocaine intake

摘要 有些人能够用可卡因等毒品进行娱乐性试验，而另一些人则会升级 他们的药物摄入量和寻求药物强迫到上瘾的地步。像瘾君子，动物自我- 服用可卡因可以调整他们的摄入量，以维持最佳的大脑可卡因和多巴胺水平， 最终决定调节行为的神经回路的神经活动模式。识别特定 负责可塑性的神经元机制控制药物摄入和药物的反馈， 寻求是理解成瘾的基础。一种非常有用的可卡因自我给药动物模型 最近开发了一种重现这种高水平、不断升级的药物摄入和药物寻求的方法。 该模型诱导大鼠在几天内逐渐将其可卡因摄入量增加到高水平， 每天允许他们6小时接触可卡因。在灭绝训练后，他们的复发反应 在几周内呈线性增长到目前为止，还没有体外研究测量了 神经生理学适应与长期访问自愿可卡因管理，也没有 任何研究都检查了消退学习逆转神经生理适应的潜力。自我 和同事（2003）已经证明了灭绝学习可以逆转诱导的几种分子变化。 并提出了消除在成瘾治疗中的作用。不幸的是， 几乎所有研究突触或内在可塑性的研究都使用非偶然的，实验者提供的 药物，它不允许灭绝学习发生。虽然有效地诱导行为可塑性，如 敏感性，非偶然性药物输送缺乏意志和动机成分，以及 奖励回路中对突触可塑性很重要的大脑区域的间歇性暂时激活。 理想情况下，一个值得研究的候选大脑区域在与升级或 可卡因渴望的潜伏期有以下标准：1）大脑内的大量神经支配 奖赏回路; 2）对奖赏刺激和条件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节; 3）在形成或储存 奖赏相关记忆; 4）奖赏回路中多巴胺神经元活动或水平的调节; 5） 双向调节消退反应的恢复（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 下托就是这样一种结构。我们过去的体外实验表明腹侧下托， 海马的主要输出结构和多巴胺系统的接口容易受到重复 精神兴奋剂诱导的可塑性本研究提出研究突触和内在兴奋性， 使用64通道平面多电极阵列组合的多巴胺对下丘脑兴奋性的调节 场电位记录和全细胞膜片钳记录在大鼠已经训练， 高/逐步增加的可卡因摄入量和在延长的戒断时间内可卡因寻求的潜伏期。灭绝 将用于逆转可卡因诱导的神经可塑性。成瘾的两个标志性特征是失去对药物摄入的控制， 复发风险高。识别大脑区域和特定的神经元 控制药物摄入和药物寻求反馈的机制是基本的 理解加法。我们的目标是利用可卡因自我管理行为 偶然意志药物摄入模型，使我们能够将可卡因摄入（低， 高或不断升级）和消除吸毒的详细措施， 神经生理学兴奋性，以便更好地了解神经系统的 与记忆相关的可塑性与成瘾有关。

Abstract Some people are capable of experimenting recreationally 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. A very useful cocaine self-administration animal model that reproduces this high, escalating level of drug intake and drug-seeking has been recently developed. This model induces rats to progressively escalate their cocaine intake to high levels over several days to weeks by allowing them 6 hour daily access to cocaine. After extinction training their relapse responding increases linearly over the course of several weeks. 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 extinction learning to reverse 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 is one such structure that does. Our past in vitro experiments have shown the ventral subiculum, the major hippocampal output structure and interface to the dopamine system to be susceptible to repeated psychostimulant-induced plasticity. This study proposes to study synaptic and intrinsic excitability and dopamine modulation of subicular excitability using a combination of 64 channel planar multielectrode array field potential recording and whole¿cell patch clamp recording in rats that have been trained for high/escalating cocaine intake and incubation of cocaine-seeking at prolonged withdrawal times. Extinction will be used to reverse the cocaine-induced neuroplasticity. 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 (low, high or escalating) and extinction of drug taking with detailed measures of neurophysiological excitability for the purposes of better understanding the neural plasticity associated with memory is linked to addiction.