Plasticity of excitability in ventral subiculum after high cocaine intake

描述（由申请人提供）：有些人可以随意地尝试毒品，比如可卡因，而另一些人则会增加他们的毒品摄入量，并强迫性地寻求毒品，直至成瘾。就像瘾君子一样，自我服用可卡因的动物会调整自己的摄入量，以保持最佳的大脑可卡因和多巴胺水平，从而最终决定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入和药物寻求反馈的可塑性的特定神经元机制是理解成瘾的基础。长时间（6小时）的可卡因自我给药动物模型再现了在戒毒期间高水平的药物摄入和增强的可卡因寻求，这在吸毒成瘾者中很常见。迄今为止，没有任何体外研究测量与长期使用可卡因相关的神经生理适应，也没有任何研究检查灭绝学习逆转神经生理适应的可能性。Self和他的同事（2003）已经证明，消退学习能够逆转由可卡因自我给药引起的一些分子变化，并提出了消退在成瘾治疗中的作用。不幸的是，几乎所有检查突触或内在可塑性的研究都使用了非偶然的、实验者给药的药物，这就不允许消退学习发生。虽然在诱导行为可塑性（如致敏）方面是有效的，但非偶然药物递送缺乏意志和动机成分，以及对突触可塑性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可卡因渴望升级或潜伏期相关的可塑性中所起的作用应符合以下标准：1)大脑奖赏回路内有大量神经支配；2)对奖励刺激、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作用；3)在奖励相关记忆的形成或储存中起作用；4)奖赏回路中多巴胺神经元活动或水平的调节；5)熄灭反应恢复的双向调控（即神经元激活触发和抑制抑制抑制恢复）。很少有大脑区域满足所有这些标准，然而，腹侧下带——主要的海马输出结构和多巴胺系统的接口——是这样一个结构。我们过去的体外实验表明腹侧下托易受反复的精神兴奋剂诱导的可塑性的影响。本研究拟研究突触和内在兴奋性以及多巴胺对腹侧海马ca1 -丘下兴奋性的调节，该兴奋性与可卡因自我给药的获得、维持和戒断/消失有关。我们将使用最先进的64通道平面多电极阵列场电位记录和全细胞膜片钳记录的组合，在短期或长期接受可卡因自我给药训练的大鼠中进行。成瘾的两个标志特征是失去控制的药物摄入和相关的高复发风险。识别控制药物摄入和药物寻求反馈的大脑区域和特定神经元机制是理解成瘾的基础。我们的目标是利用偶然自愿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摄入和药物服用的消失与神经生理兴奋性的详细测量联系起来，以便更好地理解与成瘾相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.