Plasticity of excitability in ventral subiculum after high cocaine intake

摘要 一些人能够娱乐性地尝试毒品，如可卡因，而另一些人则升级 他们吸食和寻求毒品的强迫性到了上瘾的地步。就像瘾君子一样，动物们自我 服用可卡因可调整他们的摄入量，以维持大脑中最佳的可卡因和多巴胺水平，从而 最终决定调节行为的回路中神经活动的模式。确定特定的 负责控制药物摄取和药物反馈的可塑性的神经元机制 寻找是理解成瘾的基础。一种非常有用的可卡因自我给药动物模型 这重现了最近发展起来的这种高水平、不断升级的药物摄取和寻求药物。 这个模型诱导大鼠在几天内逐渐增加可卡因的摄入量到高水平 允许他们每天6小时接触可卡因。在灭绝训练后，它们的复发反应 在几周的时间里呈线性增长。到目前为止，还没有体外研究测量过 与长时间随意使用可卡因有关的神经生理适应，也没有 任何研究都考察了灭绝学习逆转神经生理适应的可能性。自性 和他的同事们(2003)已经证明了灭绝学习可以逆转几种分子变化 通过可卡因自我管理，并提出了戒毒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，实验者提供 药物，这不允许发生灭绝学习。虽然在诱导行为可塑性方面很有效，比如 敏化，非或有药物递送缺乏意志和动机成分以及 对突触可塑性很重要的奖赏回路中大脑区域的间歇性时间激活。 理想情况下，一个值得研究的候选大脑区域在与升级或 可卡因渴求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)对奖赏刺激和条件性刺激的神经反应 它们；3)多巴胺和可卡因对神经元活动的调节；3)在脑血管形成或储存中的作用 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) 恢复已熄灭的反应的双向调节(即神经元激活触发和 抑制减少恢复)。然而，很少有大脑区域符合所有这些标准，腹侧 下丘就是这样一种结构。我们过去的体外实验表明腹侧下丘， 主要的海马体输出结构和与多巴胺系统的接口容易反复 心理刺激剂诱导的可塑性。这项研究建议研究突触和内在兴奋性，并 组合通道平面多电极阵列的多巴胺对亚束核兴奋性的调制 大鼠场电位记录和全细胞膜片钳记录 大量/不断增加的可卡因摄入量和长时间戒除可卡因的潜伏期。灭绝 将被用来逆转可卡因诱导的神经可塑性。成瘾的两个显著特征是失去受控的药物摄取和 相关的高复发风险。识别大脑区域和特定神经元 控制药物摄取和寻找反馈的机制是基本的 去理解加法。我们的目标是利用可卡因自我给药行为 偶然意志药物摄取模型，使我们能够关联可卡因摄入量(低， 高吸毒率或高吸毒率)和杜绝吸毒，并采取详细措施 为了更好地理解神经的目的的神经生理学兴奋性 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.