Cortical Plasticity in Methamphetamine Addiction

项目摘要/摘要 许多甲基苯丙胺(冰毒)成瘾者的认知障碍可能会使成瘾循环永久化。 虽然冰毒影响几个认知领域(例如，注意力、冲动、记忆)，但这种关系 认知功能受损、成瘾和复发之间的关系尚不清楚。反复使用冰毒的结果 在适应不良的大脑中，涉及识别、记忆和复发的区域的变化，包括皮质和 皮质下结构。例如，视网膜周围皮质(PRH)是参与 识别记忆并引导信息流进出海马旁结构。《医学》 前额叶皮质(MPFC)介导对冒险和药物过度消费等行为的抑制控制； 而且，伏隔核(NA)调节与奖励相关的行为。冰毒引起的这些细胞的损伤 区域导致记忆障碍、抑制控制的丧失和药物相关的偏向奖赏处理 引发旧病复发的线索。在这项提案中，我们将研究动机毒品与 服用冰毒导致认知功能障碍，并使用长通道(LA)冰毒自我管理(SA)复发 可靠地建立识别记忆缺陷并导致对寻求药物的强烈复发的养生法。 鉴于PRH是参与识别记忆的主要底物，结合我们之前的 关于冰毒引起这一区域谷氨酸生理失调的报道，我们假设冰毒会损害 识别记忆通过PRH投射神经元失去与mPFC的通讯。我们还建议 该通路包括mPFC的前臂(PL)和下臂(IL)输出，这些输出投射到 NAcore和NAShell受到冰毒的失调调节，导致对条件药物线索的恢复反应。 因此，这些独立的通路，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。然而，PRH-NAcore是一个相对未被开发的 电路和此连接的行为相关性尚未确定。我们假设这是 联系可能是冰毒诱导的认知记忆功能障碍和复发之间的统一途径。 我们的具体目标将决定冰毒是否会在参与的通路中引起功能变化 再认记忆和线索恢复。具体目标1将检验冰毒引起的假说 PRH-mPFC电路中导致识别记忆缺陷的功能变化。具体目标2 将检验这样一种假设，即mPFC-NA回路中的功能变化介导了提示的恢复 用啮齿动物的复职模式寻找冰毒。具体目标3将确定功能和 PRH-NAcore通路的行为相关性。我们假设这条途径与识别有关 记忆和对冰毒的依赖。当我们的目标完成后，我们将有一个更完整的 了解参与识别记忆和线索药物寻找的途径，以更好地提供信息 冰毒成瘾的治疗方法。

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.