Cortical Plasticity in Methamphetamine Addiction

项目总结/摘要 许多甲基苯丙胺（冰毒）成瘾者遭受认知障碍，可能会延续成瘾周期。 虽然，冰毒影响了几个认知领域（例如，注意力、冲动、记忆）， 认知功能受损、成瘾和复发之间的关系还不清楚。重复使用冰毒的结果 在适应不良的大脑中，涉及识别、记忆和复发的区域发生了变化， 皮质下结构例如，嗅周皮层（PRH）是参与神经传导的主要神经基质。 认知记忆和指导信息流入和流出海马旁结构。内侧 前额叶皮层（mPFC）介导对冒险和药物过度消费等行为的抑制控制; 此外，丘脑核（NA）调节奖赏相关行为。冰毒导致的这些 区域导致记忆缺陷，抑制控制的丧失，以及药物相关的有偏见的奖励处理。 促使复发的线索在这个建议中，我们将研究动机性药物之间的关系 服用，甲基诱导的认知功能障碍，和复发使用长时间访问（LA）甲基自我管理（SA） 该方案可靠地建立识别记忆缺陷并导致对药物寻求的稳健复发。 鉴于PRH是参与识别记忆的主要底物，结合我们之前的研究， 报告甲基诱导的谷氨酸生理失调，在这方面，我们假设，甲基损害 通过PRH投射神经元的识别记忆与mPFC失去通信。我们也建议 包括mPFC的边缘前（PL）和边缘下（IL）输出的通路投射到 NAcore和NAshell被冰毒调节异常，导致对条件药物线索的反应恢复。 因此，这些不同的通路，PRH-mPFC和mPFC-NA，表明识别记忆缺陷和 复发是成瘾病理学的不同领域。然而，PRH-NAcore是一个相对未开发的 电路和这种连接的行为相关性尚未确定。我们假设这 这种联系可能是甲基苯丙胺诱导的识别记忆功能障碍和复发之间的统一途径。 我们的具体目标将确定冰毒是否会引起参与代谢的途径内的功能变化。 再认记忆和线索复原。具体目标1将测试冰毒导致 PRH-mPFC电路内的功能变化导致识别记忆缺陷。具体目标2 将检验mPFC-NA回路内的功能变化介导的提示性恢复的假设。 用啮齿动物的复原模型来寻找冰毒具体目标3将确定功能和 PRH-NAcore通路的行为相关性。我们假设这条通路与识别有关 记忆和毒瘾复发在我们的目标完成后，我们将有一个更完整的 了解参与识别记忆和提示药物寻求的途径，以更好地了解 治疗冰毒成瘾的方法

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.