Plasticity of excitability in ventral subiculum after high cocaine intake

高可卡因摄入后腹侧下托兴奋性的可塑性

• 批准号: 7765483
• 负责人: DONALD C COOPER
• 金额: $ 30万
• 依托单位: UNIVERSITY OF COLORADO
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-04-01 至 2013-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7765483
• 关键词: Acute; Animal Model; Animals; Behavior; Behavioral; Behavioral Model; Brain; Brain region; Cocaine; Cues; Dopamine; Dose; Drug Controls; Drug Delivery Systems; Drug Exposure; Extinction (Psychology); Feedback; Goals; Hippocampus (Brain); Hour; In Vitro; Injection of therapeutic agent; Intake; Learning; Link; Measurement; Measures; Memory; Methods; Modeling; Molecular; Neuronal Plasticity; Neurons; Output; Pathway interactions; Pattern; Perforant Pathway; Pharmaceutical Preparations; Physiological; Process; Property; Rattus; Regulation; Relapse; Rewards; Risk; Role; Self Administration; Self-Administered; Signal Transduction; Slice; Stimulus; Structure; Synapses; Synaptic plasticity; Time; Training; Withdrawal; abstracting; addiction; behavioral sensitization; cocaine use; craving; dopamine system; entorhinal cortex; learning extinction; meetings; nerve supply; neural patterning; neurophysiology; patch clamp; postsynaptic; presynaptic; psychostimulant; receptor; relating to nervous system; research study; response; reward circuitry

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.

抽象的 有些人有能力使用可卡因等药物进行娱乐活动，而另一些人则升级 他们的药物摄入量并强迫毒品到成瘾点。像吸毒者一样，动物自我 管理可卡因调整其摄入量，以维持最佳的脑可卡因和多巴胺水平 最终确定调节行为的圈子中神经活动的模式。识别特定 负责控制药物摄入反馈和药物反馈的可塑性的神经元机制 寻求是理解成瘾的基础。一种非常有用的可卡因自我管理动物模型 最近已经开发了这种较高的药物摄入量和寻求药物的升级水平。 该模型引起大鼠在几天内逐渐将可卡因摄入逐渐升级到高水平 每天允许他们进入可卡因6小时的几周。延长培训后，他们的退休回应 在几周的时间里，线性增加。迄今为止，尚无体外研究测量 与长时间访问能力可卡因给药相关的神经生理适应 任何研究都检查了扩展学习的潜力，以扭转神经生理的适应性。自己 和同事（2003年）表现出扩展学习，以逆转几种分子变化引起的变化 通过可卡因自我给药，并提出了在成瘾疗法中的扩展作用。很遗憾， 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专家交付 药物，不允许扩展学习。虽然在诱导的行为可塑性方面有效，但 致敏性，非转化药物输送缺乏意志和动机成分以及 奖励电路中大脑区域的间歇性临时激活对于突触可塑性很重要。 理想情况下，一个值得调查的候选大脑区域，以在与升级相关的可塑性中发挥作用 渴望可卡因的孵化将具有以下标准； 1）大脑内的实质性神经 奖励电路； 2）对奖励刺激和条件刺激或与之相关的环境的神经反应 他们; 3）多巴胺和可卡因调节神经元活性； 3）在形成或存储中的作用 与奖励相关的记忆； 4）调节奖励电路中多巴胺神经元活性或水平； 5） 恢复灭绝反应的双向调节（即神经元激活触发器和 抑制下降恢复）。然而，很少有大脑区域符合所有这些标准 亚琴是一种这样的结构。我们过去的体外实验显示了腹侧下部。 主要海马输出结构和与多巴胺系统的接口容易重复 精神刺激诱导的可塑性。这项研究的提案要研究突触和内在的刺激性以及 使用64个通道平面多电极阵列的组合对下兴奋的多巴胺调制 现场潜在记录和全体细胞斑块夹记录已接受训练的大鼠 高/不断升级的可卡因摄入量和在长时间退出时间孵化可卡因。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受控药物摄入量和 相关的高继电器风险。识别大脑区域和特定的神经元 控制药物摄入和寻求毒品反馈的机制是基本的 了解加法。我们的目标是使用可卡因自我管理行为 偶然的意志摄入模型，使我们能够相关可卡因的摄入量（低， 高升高或升级）和延长药物服用，并详细测量 神经生理兴奋性是为了更好地理解神经元的目的 与记忆相关的可塑性与成瘾有关。