Incubated drug-craving and neurochemical interactions

潜伏的药物渴望和神经化学相互作用

• 批准号: 10543817
• 负责人: Karen Kathleen Szumlinski
• 金额: $ 33.13万
• 依托单位: UNIVERSITY OF CALIFORNIA SANTA BARBARA
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-04-15 至 2025-12-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10543817
• 关键词: AMPA Receptors; Abstinence; Address; Animal Experimentation; Animal Model; Animals; Automobile Driving; Behavior; Behavioral; Biochemical; Biochemistry; Biological Assay; Brain region; Chronic; Clinical; Cocaine; Cognitive; Cues; Data; Disease; Disease Management; Disease Progression; Disease model; Dopamine; Dopamine D1 Receptor; Dopamine Receptor; Down-Regulation; Epidemic; Exhibits; Experimental Designs; Extinction; GRM1 gene; GRM5 gene; Glutamate Receptor; Glutamates; Human; Hyperactivity; Impaired cognition; Incubated; Intake; Laboratory Animals; Learning; Link; Mediating; Mediator; Metabolic; Metabotropic Glutamate Receptors; Methamphetamine; Microdialysis; Modeling; N-Methyl-D-Aspartate Receptors; N-Methylaspartate; Nature; Neurobiology; Neurotransmitters; Pathologic; Pathology; Patients; Pharmaceutical Preparations; Predisposition; Prefrontal Cortex; Process; Psychological reinforcement; Rattus; Recording of previous events; Regulation; Relapse; Reporting; Research; Role; Scaffolding Protein; Series; Signal Transduction; Specificity; Stimulant; Sucrose; Testing; Therapeutic; Time; Treatment Efficacy; Withdrawal; Work; addiction; antagonist; base; biobehavior; cocaine craving; cocaine exposure; cocaine seeking; craving; diagnostic criteria; drug craving; drug seeking behavior; effective intervention; experience; extracellular; gamma-Aminobutyric Acid; in vivo; innovation; insight; kainate; neurochemistry; neuropathology; non-drug; novel; pharmacologic; postsynaptic; pre-clinical; psychostimulant; receptor; receptor function; reinforcer; stimulant use disorder; theories; transmission process; treatment strategy

Psychomotor-stimulant Use Disorder (PUD) is a chronic relapsing disorder, characterized by a high propensity for relapse even during protracted abstinence. In both humans with PUD & animal models, the intensity of cue- elicited drug craving & drug-seeking behavior increases or “incubates” during protracted withdrawal. The neurochemical underpinnings of drug craving & its incubation are not well understood. Drug cue-induced increase in metabolic hyperactivity within the prefrontal cortex (PFC) is correlated with the intensity of drug- craving in humans. Consistent with this, we have reported a link between the magnitude of drug-seeking in a rat model of cocaine-taking & a number of abnormalities in glutamate (GLU) transmission within the ventromedial aspect of the PFC (vmPFC). Notably, incubated cocaine-seeking is associated with a time-dependent increase in the capacity of drug-predictive cues to increase GLU levels, primarily within the prelimbic (PL) subregion. We theorize this cue-elicited rise in GLU might underpin cue-elicited increases in metabolic hyperactivity observed within PFC of PUD patients. Importantly: (1) the increased GLU responsiveness to drug-predictive cues is selective for rats with a cocaine-taking history; (2) the magnitude of the GLU increase predicts the vigor of cocaine-seeking behavior; & (3) neuropharmacological inhibition of GLU transmission within the PL eliminates cocaine-incubated responding. Intriguingly, the incubated cue-responsiveness of vmPFC GLU is inversely related to cue-elicited changes in vmPFC dopamine (DA). This inverse neurochemical relation has led to the over-arching hypothesis to be tested in this proposal: the incubation of cue-elicited drug-seeking behavior results from dysregulated GLU-DA interactions w ithin the PL subregion of the vmPFC . Aim 1 of this proposal employs neuropharmacological approaches to systematically target & dissect the relative contribution of postsynaptic AMPA & NMDA GLU receptor subtypes to the manifestation of incubated cocaine-seeking & examine for the generalization of pharmacological effects to a highly prevalent psychomotor-stimulant, methamphetamine (MA), as well as the non-drug reinforcer, sucrose. It is hypothesized in Aim 1 that the incubation of COC craving is driven by GLU-mediated activation of ionotropic GLU receptors within vmPFC. Aim 2 will employ a combination of in vivo microdialysis & neuropharmacological approaches to examine the role for D1- & D3-type DA receptors & their regulation of GLU, DA & GABA release within the vmPFC in incubated cocaine-, MA- & sucrose-seeking. It is hypothesized in Aim 2 that the incubation of cue- elicited GLU release, cellular hyperactivity & drug-seeking reflect time-dependent anomalies in DA signaling within PL. The proposal presents a series of theoretically innovative experiments designed to address the biobehavioral underpinnings of incubated craving, which will advance our basic understanding of the neurobiology of relapse.

精神运动刺激性使用障碍（PUD）是一种慢性继电器障碍，其特征是很高的诺言 即使在节制期间，也可以缓解。在两个具有PUD和动物模型的人中，提示的强度 在长期戒断期间，引起的药物渴望和寻求药物的行为增加或“孵化”。这 尚不清楚药物渴望及其孵化的神经化学基础。药物提示引起的 前额叶皮层（PFC）内代谢多动症的增加与药物的强度相关 渴望人类。与此一致，我们报告了大鼠寻求药物的大小之间的联系 可卡因的模型和腹膜内谷氨酸（GLU）的许多异常 PFC（VMPFC）的方面。值得注意的是，孵育的可卡因寻求与时间相关的增加有关 以药物预测性提示提高GLU水平的能力，主要是在前区域（PL）子区域内。我们 理论化GLU中的提示引起的上升可能是观察到的代谢多动症的提示提高的增加 在PFC的PUD患者中。重要的是：（1）GLU对药物预测提示的反应性增加是 具有可卡因历史的老鼠的选择性； （2）GLU的幅度增加了预测的活力 寻求可卡因的行为； ＆（3）PL内GLU传播的神经药理学抑制 可卡因的回应。有趣的是，VMPFC GLU的孵育的提示反应性是成反的 与VMPFC多巴胺（DA）的提示引起的变化有关。这种逆神经化学关系导致了 在此提案中要检验的规范假设： 提示吸毒行为的孵化 VMPFC的PL子区域的GLU-DA相互作用失调的结果 。目标1 提案员工的神经药理学方法系统地靶向和剖析相对贡献 突触后的AMPA和NMDA GLU受体亚型，可孵育的可卡因寻求可卡因和 检查药物效应对高度普遍的精神运动刺激剂的概括， 甲基苯丙胺（MA）以及非毒品增强剂，蔗糖。在AIM 1中假设 COC渴望的孵育是由GLU介导的离子型GLU接收器激活驱动的 VMPFC。 AIM 2将采用体内微透析和神经药物方法的组合 检查D1-和D3型DA受体的作用及其对GLU，DA和GABA释放的调节 在可卡因，ma和蔗糖寻求可卡因中的VMPFC。在AIM 2中假设 提示的孵化 引起GLU释放，细胞多动症和寻求药物反映DA中的时间依赖性异常 PL中的信号传导。 该提案提出了一系列旨在解决的理论创新实验 孵化的生物行为基础，这将提高我们对 退休神经生物学。