Cortical Plasticity in Methamphetamine Addiction

甲基苯丙胺成瘾的皮质可塑性

基本信息

批准号：
10452589
负责人：
Michael David Scofield
金额：
$ 35.51万
依托单位：
MEDICAL UNIVERSITY OF SOUTH CAROLINA
依托单位国家：
美国
项目类别：
财政年份：
2012
资助国家：
美国
起止时间：
2012-09-15 至 2024-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10452589
关键词：
Address Area Attention Behavior Behavioral Brain Brain region Chronic Cognitive Communication Consumption Cues Episodic memory Female Glutamates Goals Impaired cognition Impairment Impulsivity Long-Term Depression Medial Mediating Memory Memory impairment Mental disorders Methamphetamine Methamphetamine dependence Methamphetamine relapse Methamphetamine withdrawal Nature Neurobiology Neurons Nucleus Accumbens Outcome Study Output Pathology Pathway interactions Patients Pharmaceutical Preparations Physiology Prefrontal Cortex Rattus Regimen Regulation Relapse Reporting Research Rewards Risk Risk-Taking Rodent Rodent Model Role Self Administration Sensory Process Structure Substance Use Disorder Symptoms Testing Therapeutic Travel Treatment outcome Virus addiction behavioral pharmacology cognitive function drug abstinence functional disability improved male memory recognition methamphetamine use methamphetamine user neural circuit neuron loss neuropsychiatric disorder novel object recognition psychostimulant relating to nervous system reward processing

项目摘要

Project Summary/Abstract Many methamphetamine (meth) addicts suffer cognitive impairments that may perpetuate the addiction cycle. Although, meth impacts several cognitive domains (e.g., attention, impulsivity, memory), the relationship between impaired cognitive function, addiction, and relapse is not well understood. Repeated meth use results in maladaptive brain changes in areas involved in recognition memory and relapse including cortical and subcortical structures. For example, the perirhinal cortex (PRH) is the primary neural substrate involved in recognition memory and directs the flow of information in and out of the parahippocampal structure. The medial prefrontal cortex (mPFC) mediates inhibitory control over behaviors like risk-taking and drug over-consumption; and, the nucleus accumbens (NA) regulates reward-related behaviors. Meth induced impairments in these areas result in memory deficits, loss of inhibitory control, and biased reward processing of drug-associated cues that precipitate a relapse episode. In this proposal, we will study the relationship between motivated drug taking, meth induced cognitive dysfunction, and relapse using a long access (LA) meth self-administration (SA) regimen that reliably establishes recognition memory deficits and results in robust relapse to drug seeking. Given that the PRH is the primary substrate involved in recognition memory, combined with our previous reports of a meth-induced dysregulation of glutamate physiology in this area, we hypothesis that meth impairs recognition memory through PRH projection neurons loss of communication with the mPFC. We also suggest that the pathway encompassing prelimbic (PL) and infralimbic (IL) outputs of the mPFC that project to the NAcore and NAshell are dysregulated by meth resulting in the reinstated responding to conditioned drug cues. As such these separate pathways, PRH-mPFC and mPFC-NA, suggest that recognition memory deficits and relapse are distinct domains of the addiction pathology. However, the PRH-NAcore is a relatively unexplored circuit and the behavioral relevance of this connection has not been determined. We hypothesize that this connection may be the unifying pathway between meth-induced recognition memory dysfunction and relapse. Our Specific Aims will determine whether meth causes functional changes within the pathways involved in recognition memory and cued reinstatement. Specific Aim 1 will test the hypothesis that meth causes functional changes within the PRH-mPFC circuitry that result in recognition memory deficits. Specific Aim 2 will test the hypothesis that functional changes within the mPFC-NA circuitry mediate cued reinstatement of meth seeking using a rodent model of reinstatement. Specific Aim 3 will determine the functional and behavioral relevance of the PRH-NAcore pathway. We hypothesize that this pathway is involved in recognition memory and relapse to meth seeking. Upon completion of our aims we will have a more complete understanding of the pathways involved in recognition memory and cued drug-seeking to better inform treatment approaches for meth addiction.

项目摘要/摘要许多甲基苯丙胺（甲基苯丙胺）成瘾者遭受了可能使成瘾周期永存的认知障碍。尽管Meth会影响几个认知领域（例如，注意力，冲动性，记忆），但认知功能，成瘾和复发之间的理解尚不清楚。反复使用结果在适应不良的大脑变化中，识别记忆和复发包括皮质和复发的区域变化皮层结构。例如，周围皮质（PRH）是参与的主要神经底物识别记忆并指导信息流入和流入帕拉希公共结构。内侧前额叶皮层（MPFC）介导对冒险和药物过度消耗等行为的抑制控制；并且，伏隔核（NA）调节与奖励相关的行为。甲基甲基诱导的损害区域导致记忆缺陷，抑制性控制的丧失以及与药物相关的偏见奖励处理引起复发发作的提示。在此提案中，我们将研究积极的药物之间的关系采取，甲基苯丙胺引起的认知功能障碍，并使用长途访问（LA）甲基化（SA）复发可靠地确定识别记忆缺陷并导致对毒品寻求药物的稳健复发的方案。鉴于PRH是识别记忆中涉及的主要基材，与我们以前的甲基苯甲酸盐诱导的谷氨酸生理失调的报道，我们假设甲基通过PRH投影神经元与MPFC进行通信的识别记忆。我们也建议该途径涵盖了MPFC的MPFC的前提（PL）和Infralimbic（IL）输出 Nacore和Nashell因甲基苯丙胺失调，导致对条件药物提示的响应。因此，这些单独的途径，PRH-MPFC和MPFC-NA，表明识别记忆缺陷和复发是成瘾病理的不同领域。但是，PRH-NACORE是一个相对尚未探索的尚未确定电路和该连接的行为相关性。我们假设这是连接可能是Meth诱导的识别记忆功能障碍和复发之间的统一途径。我们的具体目的将确定甲基苯丙胺是否在涉及的途径内引起功能变化识别记忆和提示恢复原状。特定目标1将检验甲基甲基甲基苯丙胺原因的假设 PRH-MPFC电路中导致识别记忆缺陷的功能变化。具体目标2 将检验以下假设：MPFC-NA电路内的功能变化介导了提示的恢复使用啮齿动物恢复模型寻求冰毒。特定目标3将决定功能，并且 PRH-NACORE途径的行为相关性。我们假设该途径参与了认可记忆和寻求甲基苯丙胺的复发。完成目标后，我们将获得更完整的了解识别记忆和寻求毒品的涉及的途径以更好地告知甲基成瘾的治疗方法。