Synaptic mechanisms underlying reward seeking and compulsive drug use

奖励寻求和强迫性药物使用的突触机制

• 批准号: 8941392
• 负责人: Veronica A Alvarez
• 金额: $ 107.97万
• 依托单位: NATIONAL INSTITUTE ON ALCOHOL ABUSE AND ALCOHOLISM
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/8941392
• 关键词: AMPA Receptors; Acute; Affect; Agonist; Alcohol consumption; Alcohols; Behavior; Behavioral; Blood; Brain; Chronic; Circadian Rhythms; Cocaine; Cocaine Abuse; Consumption; Corpus striatum structure; DRD2 gene; Depressed mood; Development; Dopamine; Dopamine Receptor; Drug effect disorder; Drug usage; Ethanol; Feedback; Fiber; Genetic; Glutamates; Goals; Hour; In Vitro; Individual; Intoxication; Laboratories; Length; Locomotion; Measures; Mediating; Mental Depression; Midbrain structure; Modeling; Morphology; Mouse Strains; Mus; N-Methyl-D-Aspartate Receptors; Neurobiology; Neurons; Neurosciences; Nucleus Accumbens; Pattern; Pharmaceutical Preparations; Physiologic pulse; Physiological; Population; Property; Recovery; Research; Resolution; Rewards; Role; Scanning; Signal Transduction; Slice; Speed; Structure; Synapses; Synaptic Transmission; Time; Ventral Tegmental Area; Vertebral column; Whole-Cell Recordings; addiction; alcohol use disorder; density; dopaminergic neuron; drinking; drinking behavior; in vivo; motivated behavior; motor impairment; neural circuit; novel; optogenetics; preference; presynaptic; prevent; response; reuptake; success; synaptic function; tool; transmission process

Project 1: Glutamate and dopamine transmission from midbrain dopamine neurons share similar release properties but are differentially affected by cocaine.(Adrover, Shin and Alvarez, J. Neuroscience 2014)Synaptic transmission between ventral tegmental area and nucleus accumbens (NAc) is critically involved in reward-motivated behaviors and thought to be altered in addiction. In addition to dopamine (DA), glutamate is packaged and released by a subset of mesolimbic DA neurons, eliciting EPSCs onto medium spiny neurons in NAc. Little is known about the properties and modulation of glutamate release from DA midbrain terminals and the effect of cocaine. Using an optogenetic approach to selectively activate midbrain DA fibers, we compared the properties and modulation of DA transients and EPSCs measured using fast-scan cyclic voltammetry and whole-cell recordings in mouse brain slices. DA transients and EPSCs were inhibited by DA receptor D2R agonist and showed a marked paired-pulse depression that required 2 min for full recovery. Cocaine depressed EPSCs amplitude by 50% but enhanced the overall DA transmission from midbrain DA neurons. AMPA and NMDA receptor-mediated EPSCs were equally inhibited by cocaine, suggesting a presynaptic mechanism of action. Pharmacological blockage and genetic deletion of D2R in DA neurons prevented the cocaine-induced inhibition of EPSCs and caused a larger increase in DA transient peak, confirming the involvement of presynaptic D2R. These findings demonstrate that acute cocaine inhibits DA and glutamate release from midbrain DA neurons via presynaptic D2R but has differential overall effects on their transmissions in the NAc. We postulate that cocaine, by blocking DA reuptake, prolongs DA transients and facilitates the feedback inhibition of DA and glutamate release from these terminals. Project 2: Repeated binge-like ethanol drinking alters ethanol drinking patterns and depresses striatal GABAergic transmission.(Wilcox et al., Neuropsychopharmacology 2014) Research into the neurobiology of heavy and binge-like ethanol drinking has been limited by the low-levels of voluntary ethanol consumption shown by most mouse strains (Crabbe et al., 2011). Recently, a model of intermittent access to ethanol has been shown to elicit binge-like drinking and pharmacologically relevant blood ethanol concentrations (BECs) in mice (Rhodes et al., 2005). Termed Drinking in the Dark, this model takes advantage of the circadian patterns of mice to achieve reliably high levels of consumption in a two hour drinking session. C57BL/6J mice reach BECs higher than 80 mg/dl, and show signs of intoxication such as motor impairment (Rhodes et al., 2007). DID is a robust paradigm that has been successfully used to investigate neuronal circuits and signals that modulate binge-like ethanol consumption (Sprow, 2012). Despite the success of this intermittent access model, the mechanisms underlying the acquisition of voluntary ethanol drinking are not completely understood. In this study, we established DID in our laboratory and showed that it produces reliable escalation of voluntary ethanol intake and blood ethanol concentration. We characterized the drinking pattern of mice with intermittent access to ethanol using lickometers to record each bout with high temporal resolution over many weeks of voluntary ethanol consumption, and analyzed the synaptic morphology of striatal neurons 2 days and 30 days after the last ethanol binge. The results represent a novel and important contribution to the alcohol field because they identify the bottle exchange, an integral part of DID, as a likely mechanism by which intermittent access facilitates the acquisition of voluntary ethanol drinking behavior by inducing mice to drink at a higher rate. Over time, mice change their ethanol drinking pattern and increase the speed of drinking at the beginning of each DID session. Faster ethanol drinking is associated with higher BEC, and an enhanced preference for ethanol was observed after 6 weeks of treatment. Interestingly, no changes were detected in either striatal or accumbal spine density, and a shortening of spine length was seen only transiently, suggesting that these behavioral changes occur independent of long-term changes in synaptic morphology in brain.

项目 1：中脑多巴胺神经元的谷氨酸和多巴胺传递具有相似的释放特性，但受可卡因的影响不同。（Adrover、Shin 和 Alvarez, J. Neuroscience 2014）腹侧被盖区和伏隔核 (NAc) 之间的突触传递至关重要奖励驱动的行为并被认为会在成瘾中改变。除了多巴胺 (DA) 之外，谷氨酸也由中脑边缘 DA 神经元的子集包装和释放，从而引发 EPSC 到 NAc 中的中型多棘神经元上。关于 DA 中脑末梢释放谷氨酸的特性和调节以及可卡因的作用，人们知之甚少。使用光遗传学方法选择性激活中脑 DA 纤维，我们比较了使用快速扫描循环伏安法和小鼠脑切片中的全细胞记录测量的 DA 瞬变和 EPSC 的特性和调制。 DA 瞬变和 EPSC 被 DA 受体 D2R 激动剂抑制，并显示出明显的配对脉冲抑制，需要 2 分钟才能完全恢复。可卡因使 EPSC 振幅降低 50%，但增强了中脑 DA 神经元的整体 DA 传输。 AMPA 和 NMDA 受体介导的 EPSC 同样受到可卡因的抑制，表明其存在突触前作用机制。 DA 神经元中 D2R 的药理学阻断和基因删除阻止了可卡因诱导的 EPSC 抑制，并导致 DA 瞬时峰值大幅增加，证实了突触前 D2R 的参与。这些发现表明，急性可卡因通过突触前 D2R 抑制中脑 DA 神经元释放 DA 和谷氨酸，但对它们在 NAc 中的传输具有不同的总体影响。我们假设可卡因通过阻断 DA 再摄取，延长 DA 瞬态并促进 DA 和谷氨酸从这些末端释放的反馈抑制。 项目 2：反复暴饮暴食乙醇会改变乙醇饮用模式并抑制纹状体 GABA 能传递。（Wilcox 等人，Neuropsychopharmacology 2014） 对大量和狂饮乙醇的神经生物学研究受到大多数小鼠品系显示的低水平自愿乙醇消耗的限制（Crabbe 等，2011）。最近，间歇性摄入乙醇的模型已被证明会引起小鼠的暴饮暴食和药理学相关的血液乙醇浓度（BEC）（Rhodes 等，2005）。该模型被称为“黑暗中饮酒”，利用小鼠的昼夜节律模式在两小时的饮酒过程中实现可靠的高水平消耗。 C57BL/6J 小鼠的 BEC 达到高于 80 mg/dl，并显示出中毒迹象，例如运动障碍（Rhodes 等，2007）。 DID 是一种强大的范例，已成功用于研究调节暴饮暴食型乙醇消耗的神经元回路和信号（Sprow，2012）。尽管这种间歇性获取模式取得了成功，但自愿饮用乙醇的机制尚不完全清楚。在这项研究中，我们在实验室建立了 DID，并表明它可以可靠地提高自愿乙醇摄入量和血液乙醇浓度。我们使用舔度计对间歇性摄入乙醇的小鼠的饮酒模式进行了表征，以高时间分辨率记录自愿乙​​醇消耗数周内的每次发作，并分析了最后一次乙醇暴饮后 2 天和 30 天纹状体神经元的突触形态。这些结果对酒精领域做出了新颖且重要的贡献，因为他们发现瓶子交换是 DID 的一个组成部分，它是一种可能的机制，通过该机制间歇性获取通过诱导小鼠以更高的速率饮酒来促进自愿乙醇饮酒行为的获得。 随着时间的推移，小鼠会改变其乙醇饮用模式，并在每次 DID 开始时加快饮用速度。 更快地饮用乙醇与更高的 BEC 相关，并且在治疗 6 周后观察到对乙醇的偏好增强。有趣的是，纹状体或伏节棘密度均未检测到变化，并且仅短暂地观察到棘长度的缩短，这表明这些行为变化的发生与大脑突触形态的长期变化无关。