Incubated drug-craving and neurochemical interactions

精神运动兴奋剂使用障碍(PUD)是一种慢性复发性障碍，以高倾向性为特征 即使在长期禁欲期间也不会复发。在患有PUD和动物模型的人类中，线索的强度- 诱发的药物渴求&在长期戒断过程中，寻求毒品的行为增加或“潜伏”。这个 药物渴求及其孵化的神经化学基础还不是很清楚。药物线索诱导 前额叶皮质(PFC)内代谢亢进的增加与药物的强度有关- 人类的渴望。与此一致，我们已经报道了在老鼠身上寻找药物的程度之间的联系 可卡因摄取模型&腹内侧区谷氨酸(GLU)传递的若干异常 PFC(VmPFC)的一个方面。值得注意的是，孵化的可卡因寻找与时间相关的增加有关。 药物预测线索增加GLU水平的能力，主要是在初步(PL)次区域内。我们 理论上，这种线索诱导的血糖升高可能支持线索诱导的代谢性多动增加观察到的 在PUD患者的PFC内。重要的是：(1)GLU对药物预测线索的反应增加是 对有可卡因吸毒史的大鼠有选择性；(2)GLU增加的幅度预测了 寻找可卡因的行为；&(3)神经药物抑制PL内的GLU传递可消除 可卡因孵化的反应。有趣的是，vmPFC GLU的孵化线索反应性与之相反 与线索诱导的vmPFC多巴胺(DA)变化有关。这种反向的神经化学关系导致了 将在本提案中测试的总体假设： 线索诱导型寻药行为的孵化 VmPFC的PL亚区与GLU-DA相互作用失调的结果 。目标1 Proposal使用神经药理学方法系统地针对和剖析相对贡献 突触后AMPA和NMDAGLU受体亚型与潜伏期寻找可卡因的关系 研究一种高度流行的精神运动兴奋剂的药理作用， 甲基苯丙胺(MA)，以及非药物增强剂蔗糖。在目标1中假设 COC渴求的孵化是由GLU介导的体内离子型GLU受体的激活驱动的 VmPFC。AIM 2将采用体内微透析和神经药理学方法相结合的方法来 探讨D_1和D_3型DA受体的作用及其对脑内GLU、DA和GABA释放的调节 VmPFC在培养的可卡因、MA和蔗糖寻找中。《目标2》中假设 线索的孵化- 诱发的GLU释放、细胞过度活动和药物寻找反映DA的时间依赖性异常 在PL内发送信号。 该提案提出了一系列理论上的创新实验，旨在解决 潜伏的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.