Involvement of the orbitofrontal cortex in relapse to cocaine-seeking behaviors

眶额皮质参与可卡因寻求行为的复发

• 批准号: 8271252
• 负责人: Heather Lasseter
• 金额: $ 1.67万
• 依托单位: UNIV OF NORTH CAROLINA CHAPEL HILL
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-07-01 至 2011-12-18
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8271252
• 关键词: Abbreviations; Addictive Behavior; Amygdaloid structure; Behavior; Behavioral; Brain; Brain region; Brain-Derived Neurotrophic Factor; Cocaine; Cocaine Dependence; Cocaine Users; Cognitive; Cues; Dorsal; Drug user; Elements; Exhibits; Extinction (Psychology); Fiber; Health; Hearing; Hippocampus (Brain); Histocytochemistry; Human; Hypothalamic structure; Immediate-Early Genes; In Situ Hybridization; Indium; Individual; Infusion procedures; Lateral; Lead; Leg; Lesion; Messenger RNA; Modeling; Molecular; Motivation; N-Methylaspartate; National Institute of Drug Abuse; Neurobiology; Neuronal Plasticity; Nucleus Accumbens; Output; Pathology; Pharmaceutical Preparations; Prefrontal Cortex; Psychological reinforcement; Rattus; Relapse; Relative (related person); Rodent Model; Self Administration; Self-Administered; Site; Stress; Substantia nigra structure; Testing; Time; Training; United States; Ventral Tegmental Area; Withdrawal; Zinc Fingers; addiction; base; behavioral impairment; cocaine use; craving; disorder later incidence prevention; drug mechanism; drug relapse; drug seeking behavior; experience; frontal lobe; innovation; insight; mRNA Expression; neuroadaptation; neuromechanism; novel; prevent; public health relevance; relating to nervous system; research study; reward circuitry; social; therapy development; treatment strategy

DESCRIPTION (provided by applicant): Damage to the orbitofrontal cortex (OFC) may contribute to persistent craving and compulsive drug seeking in former drug users. Consistent with this, lOFC lesions induced prior to self-administration training potentiate context-induced cocaine seeking in a rat model of drug relapse. The guiding hypothesis of this proposal is that prolonged loss of output from the lOFC enhances context-induced motivation for cocaine by eliciting compensatory neuroadaptations in other elements of the brain circuitry of drug relapse. Overall, this proposal will utilize the contextual extinction-reinstatement model of drug relapse in which rats are trained to self-administer cocaine in a distinct environmental context, followed by extinction training in a different context. Context-induced motivation for cocaine is then assessed in the cocaine-paired context in the absence of cocaine reinforcement. Specific Aim 1 will test the hypothesis that pre-training lOFC lesions prompt enhanced context-induced motivation for cocaine and associated compensatory neuroadaptations in immediate-early gene (lEG) expression in elements of the mesocorticolimbic relapse circuitry. To this end, we will administer lesions of the lOFC prior to cocaine self-administration training and then use in situ hybridization histochemistry to assess mRNA expression of the activity-dependent lEG zinc finger 268 (zif268) and brain-derived neurotrophic factor (BDNF), following reinstatement testing in the cocaine-paired context. Specific Aim 2 will test the hypothesis that reversing lOFC lesion-induced increases in zif268 and BDNF expression in critical brain regions will abolish lOFC lesion-induced enhancement in context-induced motivation for cocaine. To assess whether lOFC lesion-induced increases in lEG expression are necessary for enhanced context-induced reinstatement, immediately before reinstatement testing, rats with pre-training lOFC lesions will receive zif268 or BDNF antisense oligodeoxynucleotide infusions into brain regions that exhibit the most robust elevation in zif268 or BDNF expression in the lOFC lesion vs. sham groups. Public Health Relevance: Cocaine addiction is a prominent health and social issue in the United States, with about 1.6 million individual classified as cocaine dependent (2007 NSDUH, NIDA). OFC damage in cocaine addicts has been theorized to promote addictive behavior and the proposed project utilizes a rodent model of drug relapse to explore the cellular and functional neuroanatomical mechanisms of this phenomenon. Understanding the neural mechanisms underlying of OFC lesion-induced loss of control in drug seeking may offer critical insight for addiction treatment development.

描述（由申请人提供）：轨道额皮层（OFC）的损害可能有助于前吸毒者持续渴望和强迫性毒品。与此一致，在自我管理训练训练之前引起的LOFC病变增强了上下文引起的可卡因在药物复发模型中寻求。该提议的指导假设是，LOFC的长期输出量长期损失通过在药物复发的其他​​元素中引起其他元素，从而增强了上下文引起的可卡因动机。总体而言，该提案将利用上下文灭绝 - 复发模型，在该模型中，在独特的环境环境中对大鼠进行自我管理的可卡因训练，然后在不同的情况下进行灭绝训练。然后在不存在可卡因增强的情况下，在可卡因对的上下文中评估了上下文引起的可卡因动机。具体目标1将检验以下假设：预训练LOFC病变促使上下文引起的可卡因动机和相关的补偿性神经适应性的动机，在中心层状复发回路元素中的即时基因表达（腿）表达。为此，我们将在可卡因自我给药训练之前对LOFC进行病变，然后使用原位杂交组织化学来评估活性依赖性腿部锌指268（ZIF268）（ZIF268）和脑源性神经营养因子（BDNF）的mRNA表达，并在重新施加后的cocecececececececececececececececececececececececectectectectsectectectect中。具体目标2将检验以下假设：逆转loFC病变诱导的ZIF268和临界大脑区域BDNF表达的增加将废除LOFC病变诱导的可卡因动机的增强。为了评估LOFC病变诱导的腿表达增加是在恢复测试之前的上下文诱导的恢复是否需要的，具有预训练的LOFC病变的大鼠将接受ZIF268或BDNF反义寡氧化核苷酸的大脑区域，表现为在ZIF268中表现出最稳健的脑区域，或者在Z568中表现出ZIF268或BDNF的表达。组。公共卫生相关性：可卡因成瘾是美国的重要健康和社会问题，约有160万个人被归类为可卡因依赖性（2007年NSDUH，NIDA）。可卡因上瘾者中的OFC损害已被理论上促进上瘾的行为，而拟议的项目利用药物复发的啮齿动物模型来探索这种现象的细胞和功能性神经解剖机制。了解OFC病变诱导的吸毒控制丧失的神经机制可能为成瘾治疗发展提供了关键的见解。