Incubated drug-craving and neurochemical interactions

精神运动兴奋剂使用障碍（PUD）是一种慢性复发性疾病，其特征是高倾向性 即使在长期禁欲期间也会复发。在PUD患者和动物模型中，提示的强度- 诱发的药物渴望&在长期戒断期间，寻求药物的行为增加或“潜伏”。的 药物渴求的神经化学基础及其潜伏期还没有得到很好的理解。药物线索诱导 前额叶皮层（PFC）内代谢亢进的增加与药物的强度相关， 人类的渴望与此相一致，我们已经报道了大鼠的药物寻求程度与 可卡因摄入模型&腹内侧核谷氨酸（GLU）传递的一些异常 PFC（vmPFC）。值得注意的是，孵化可卡因寻求与时间依赖性增加有关 药物预测线索增加GLU水平的能力，主要是在前边缘（PL）子区域内。我们 理论上，这种提示引起的GLU升高可能支持观察到的提示引起的代谢亢进增加 在PUD患者的PFC中。重要的是：（1）GLU对药物预测线索的反应性增加， 选择性的大鼠可卡因服用史;（2）GLU增加的幅度预测的活力， 可卡因寻求行为;（3）PL内GLU传递的神经药理学抑制消除了 可卡因孵育的反应有趣的是，vmPFC GLU的孵育提示反应性与 与提示诱发的vmPFC多巴胺（DA）变化有关。这种逆神经化学关系导致了 本提案中要检验的过度假设： 线索诱导的寻药行为的潜伏期 结果与vmPFC的PL亚区的GLU-DA相互作用失调 .目标1 建议采用神经药理学方法系统地靶向和剖析相对贡献 突触后AMPA和NMDA GLU受体亚型的表现，孵化可卡因寻求和 检查药理作用对高度流行的精神运动兴奋剂的概括， 甲基苯丙胺（MA），以及非药物兴奋剂蔗糖。目标1假设， COC渴求的孵化是由Glu介导的离子型GLU受体的激活驱动的， vmPFC。目标2将采用体内微透析和神经药理学方法相结合， 研究D1和D3型DA受体的作用及其对GLU，DA和GABA释放的调节， 在孵育的可卡因、MA和蔗糖寻找中的vmPFC。目标2假设， cue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内的信号。 该提案提出了一系列理论上的创新实验，旨在解决 孵化渴望的生物行为基础，这将促进我们对 复发的神经生物学

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.