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

基本信息

批准号：
7480823
负责人：
DONALD C COOPER
金额：
$ 27.48万
依托单位：
UT SOUTHWESTERN MEDICAL CENTER
依托单位国家：
美国
项目类别：
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/7480823
关键词：
Action Potentials Acute Animal Model Animals Arts Behavior Behavioral Behavioral Model Brain Brain region Cells Cocaine Condition Daily Dendritic Spines Dopamine Drug Controls Drug Delivery Systems Extinction (Psychology)Feedback Goals Hippocampal Formation Hippocampus (Brain)In Vitro Intake Link Maintenance Measurement Measures Membrane Memory Modeling Molecular Morphology Neuronal Plasticity Neurons Output Pathway interactions Pattern Pharmaceutical Preparations Phase Physiology Property Purpose Range Rattus Regulation Relapse Reporting Rewards Risk Role Saline Self Administration Self-Administered Signal Transduction Slice Stimulus Structure Synapses Synaptic plasticity Techniques Time Training Whole-Cell Recordings Withdrawal addiction craving density dopamine system dopaminergic neuron drug abstinence drug addict hippocampal pyramidal neuron in vivo learning extinction nerve supply neuronal excitability neurophysiology patch clamp postsynaptic presynaptic psychostimulant relating to nervous system research study response reward circuitry

Action Potentials Acute Animal Model Animals Arts Behavior Behavioral Behavioral Model Brain Brain region Cells Cocaine Condition Daily Dendritic Spines Dopamine Drug Controls Drug Delivery Systems Extinction (Psychology)Feedback Goals Hippocampal Formation Hippocampus (Brain)In Vitro Intake Link Maintenance Measurement Measures Membrane Memory Modeling Molecular Morphology Neuronal Plasticity Neurons Output Pathway interactions Pattern Pharmaceutical Preparations Phase Physiology Property Purpose Range Rattus Regulation Relapse Reporting Rewards Risk Role Saline Self Administration Self-Administered Signal Transduction Slice Stimulus Structure Synapses Synaptic plasticity Techniques Time Training Whole-Cell Recordings Withdrawal addiction craving density dopamine system dopaminergic neuron drug abstinence drug addict hippocampal pyramidal neuron in vivo learning extinction nerve supply neuronal excitability neurophysiology patch clamp postsynaptic presynaptic psychostimulant relating to nervous system research study response reward circuitry

展开

项目摘要

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.

描述（由申请人提供）：有些人能够随便尝试可卡因，而另一些人则可以升级其毒品摄入量并强迫毒品到成瘾点。像瘾君子一样，动物自我管理可卡因会调整其摄入量，以维持最佳的脑可卡因和多巴胺水平，这些水平最终决定了调节行为的电路中神经活动的模式。确定负责控制对药物摄入和寻求药物反馈的可塑性的特定神经元机制对于理解成瘾是至关重要的。可卡因自我给药的延长（6小时）的动物模型在药物瘾者经常看到的药物戒酒期间再现了高水平的药物摄入量和增强的可卡因寻求可卡因。迄今为止，尚无体外研究测量与延长访问能力可卡因给药相关的神经生理适应，也没有任何研究检查灭绝的潜力，以扭转神经生理的适应性。 Self及其同事（2003年）表明，灭绝学习能够逆转可卡因自我给药引起的几种分子变化，并提出了在成瘾疗法中灭绝的作用。不幸的是，几乎所有检查突触可塑性或内在可塑性的研究都使用了非转化器，实验者递送的药物，这不允许灭绝学习。虽然有效诱导行为可塑性，但如敏化，非传染性药物的递送缺乏自愿性和动机成分，以及奖励电路中大脑区域的间歇性时间激活对突触可塑性很重要。理想情况下，值得研究与可卡因渴望升级或孵化相关的可塑性中作用的候选大脑区域将具有以下标准； 1）大脑奖励电路内的实质性神经； 2）对奖励刺激和条件刺激或与之相关的环境的神经反应； 3）多巴胺和可卡因调节神经元活性； 3）在与奖励相关记忆的形成或存储中的作用； 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（即神经元激活触发和抑制作用降低了恢复）。但是，很少有大脑区域符合所有这些标准，但是，腹侧下调（主要的海马输出结构和多巴胺系统的界面）就是这样的结构。我们过去的体外实验表明，腹侧下调易受重复的精神刺激诱导的可塑性。这项研究建议研究与可卡因自我给药的获取，维持和戒断/灭绝相关的腹侧海马CA1-宽带兴奋性的突触和多巴胺调节。我们将使用最先进的64通道平面多电极阵列电位录制和全细胞贴片夹在大鼠中的组合，这些记录已接受训练，这些大鼠经过了训练，这些记录是经过训练的，可以简短访问或长时间访问可卡因自我管理。成瘾的两个标志性特征是受控药物摄入量的丧失和相关的高复发风险。确定控制药物摄入和寻求药物反馈的大脑区域和特定的神经元机制对于理解添加至关重要。我们的目标是使用可卡因的自我管理行为模型的偶然性意志摄入量的行为模型，以使我们能够将可卡因的摄入量和吸毒的灭绝与神经生理兴奋性的详细指标相关联，以更好地了解与与成瘾相关的记忆相关的神经可变性。