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.

精神运动兴奋剂使用障碍 (PUD) 是一种慢性复发性疾病，其特点是高度倾向 在患有 PUD 的人类和动物模型中，即使在长期禁欲期间也会复发。 在长期戒断过程中，引起的药物渴望和寻求药物的行为会增加或“潜伏”。 药物渴望及其孵化的神经化学基础尚不清楚。 前额皮质（PFC）内代谢亢进的增加与药物的强度相关。 与此相一致的是，我们报道了老鼠寻求药物的程度之间的联系。 可卡因摄入模型和腹内侧谷氨酸 (GLU) 传输的一些异常 值得注意的是，寻求可卡因与时间依赖性增加有关。 药物预测线索能够增加 GLU 水平，主要是在前边缘 (PL) 次区域。 理论上，这种由线索引起的 GLU 上升可能是由线索引起的代谢亢进增加的基础 PUD 患者的 PFC 内重要的是：（1）GLU 对药物预测线索的反应性增加。 对有吸食可卡因史的大鼠具有选择性；(2) GLU 增加的幅度可预测其活力。 (3) PL 内 GLU 传输的神经药理学抑制消除 有趣的是，vmPFC GLU 的孵化提示反应性是相反的。 与线索引起的 vmPFC 多巴胺 (DA) 变化有关，这种反向神经化学关系导致了 本提案要测试的总体假设： 线索引发的寻药行为的孕育 GLU-DA 与 vmPFC PL 亚区相互作用失调的结果 .目标1 提案采用神经药理学方法来系统地定位和剖析相对贡献 突触后 AMPA 和 NMDA GLU 受体亚型与中毒可卡因寻求表现的关系 检查对高度流行的精神运动兴奋剂的药理作用的普遍性， 甲基苯丙胺 (MA) 以及非药物强化剂蔗糖 目标 1 中重申了 COC渴望的孵化是由GLU介导的离子型GLU受体激活驱动的 vmPFC。目标 2 将采用体内微透析和神经药理学方法相结合 检查 D1 和 D3 型 DA 受体的作用及其对 GLU、DA 和 GABA 释放的调节 vmPFC 在诱导可卡因、MA 和蔗糖寻找中再次出现在目标 2 中。 提示的孵化 引起的 GLU 释放、细胞过度活跃和药物寻求反映了 DA 中的时间依赖性异常 PL 内的信令。 该提案提出了一系列理论上创新的实验，旨在解决 孵化渴望的生物行为基础，这将增进我们对 复发的神经生物学。