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:
- 金额:$ 27.48万
- 依托单位:
- 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:
- 关键词:Action PotentialsAcuteAnimal ModelAnimalsArtsBehaviorBehavioralBehavioral ModelBrainBrain regionCellsCocaineConditionDailyDendritic SpinesDopamineDrug ControlsDrug Delivery SystemsExtinction (Psychology)FeedbackGoalsHippocampal FormationHippocampus (Brain)In VitroIntakeLinkMaintenanceMeasurementMeasuresMembraneMemoryModelingMolecularMorphologyNeuronal PlasticityNeuronsOutputPathway interactionsPatternPharmaceutical PreparationsPhasePhysiologyPropertyPurposeRangeRattusRegulationRelapseReportingRewardsRiskRoleSalineSelf AdministrationSelf-AdministeredSignal TransductionSliceStimulusStructureSynapsesSynaptic plasticityTechniquesTimeTrainingWhole-Cell RecordingsWithdrawaladdictioncravingdensitydopamine systemdopaminergic neurondrug abstinencedrug addicthippocampal pyramidal neuronin vivolearning extinctionnerve supplyneuronal excitabilityneurophysiologypatch clamppostsynapticpresynapticpsychostimulantrelating to nervous systemresearch studyresponsereward circuitry
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):有些人能够随意尝试毒品,如可卡因,而另一些人则增加他们的药物摄入量,并强迫性地寻求药物成瘾。像成瘾者一样,自我服用可卡因的动物会调整摄入量,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。可卡因自我给药的延长(6小时)接触动物模型再现了在药物成瘾者中常见的药物戒断期间的高水平药物摄入和增强的可卡因寻求。到目前为止,没有体外研究测量与长期访问自愿可卡因管理相关的神经生理学适应,也没有任何研究检查消退学习逆转神经生理学适应的潜力。Self及其同事(2003)已经证明,消退学习能够逆转可卡因自我给药引起的几种分子变化,并提出了消退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了非偶然的,实验者提供的药物,这不允许灭绝学习发生。虽然有效地诱导行为可塑性,如敏化,非偶然的药物输送缺乏意志和动机的组成部分,以及间歇性的时间激活的大脑区域的奖励电路重要的突触可塑性。理想情况下,一个值得研究的候选脑区在与可卡因渴望的升级或潜伏期相关的可塑性中的作用将具有以下标准:1)大脑奖励回路内的实质性神经支配; 2)对奖励刺激和条件刺激或与其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)在奖赏相关记忆的形成或储存中的作用; 4)调节奖赏回路中多巴胺神经元的活动或水平; 5)双向调节熄灭的反应的恢复(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--海马体的主要输出结构和多巴胺系统的接口--就是这样一个结构。我们过去的体外实验表明,腹侧下托是易受反复精神兴奋剂诱导的可塑性。本研究拟研究腹侧海马CA 1-下托兴奋性的突触和内在兴奋性和多巴胺调制,与可卡因自我给药的获得,维持和戒断/消退相关。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,在大鼠中,已被训练为短期访问或长期访问可卡因自我管理。成瘾的两个标志性特征是失去控制的药物摄入和相关的高复发风险。确定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加法的基础。我们的目标是使用可卡因自我管理行为模型的偶然意志药物摄入量,使我们能够关联可卡因的摄入量和药物服用的消退与详细的神经生理兴奋性的措施,更好地了解与成瘾相关的记忆的神经可塑性。
项目成果
期刊论文数量(0)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
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DONALD C COOPER其他文献
DONALD C COOPER的其他文献
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{{ truncateString('DONALD C COOPER', 18)}}的其他基金
Pathway specific ecstasy-induced plasticity of excitability in the subiculum
途径特异性摇头丸诱导的下托兴奋性可塑性
- 批准号:
7636741 - 财政年份:2008
- 资助金额:
$ 27.48万 - 项目类别:
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:
7586641 - 财政年份:2008
- 资助金额:
$ 27.48万 - 项目类别:
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:
8079336 - 财政年份:2008
- 资助金额:
$ 27.48万 - 项目类别:
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 - 财政年份:2008
- 资助金额:
$ 27.48万 - 项目类别:
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:
8033756 - 财政年份:2008
- 资助金额:
$ 27.48万 - 项目类别:
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:
7907290 - 财政年份:2008
- 资助金额:
$ 27.48万 - 项目类别:
Pathway specific ecstasy-induced plasticity of excitability in the subiculum
途径特异性摇头丸诱导的下托兴奋性可塑性
- 批准号:
7536111 - 财政年份:2008
- 资助金额:
$ 27.48万 - 项目类别:
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:
8220831 - 财政年份:2008
- 资助金额:
$ 27.48万 - 项目类别:
DNA Microarray Analysis of Neuronal Excitability
神经元兴奋性的 DNA 微阵列分析
- 批准号:
7990916 - 财政年份:2005
- 资助金额:
$ 27.48万 - 项目类别:
DNA Microarray Analysis of Neuronal Excitability
神经元兴奋性的 DNA 微阵列分析
- 批准号:
7066048 - 财政年份:2005
- 资助金额:
$ 27.48万 - 项目类别:
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