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的传播具有相似的释放特性，但受可卡因的差异影响（Adrover，Shin和Alvarez，J。Neuroscience 2014）腹侧置换区域与核accumbens（NAC）（NAC）之间的突触传播涉及奖励的行为，并涉及奖励的行为，并涉及奖励行为。除多巴胺（DA）外，谷氨酸还通过中唇DA神经元的子集包装并释放，并将EPSC诱导到NAC中的中棘神经元上。关于从DA中脑末端释放谷氨酸释放的性质和调节以及可卡因的效果，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的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的特性和调节。 DA受体D2R激动剂抑制了DA瞬变和EPSC，并显示出明显的配对脉冲抑制，需要2分钟才能完全恢复。可卡因抑郁EPSC幅度幅度增加了50％，但增强了中脑DA神经元的总体DA传播。可卡因同样抑制AMPA和NMDA受体介导的EPSC，这表明是突触前作用机理。 DA神经元中D2R的药理学阻塞和遗传缺失阻止了可卡因诱导的EPSC抑制，并导致DA瞬时峰的增加，从而证实了突触前D2R的参与。这些发现表明，急性可卡因通过突触前D2R抑制DA和谷氨酸从中脑DA神经元释放，但对NAC中的传播具有不同的总体影响。我们假设可卡因通过阻止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：重复的暴饮暴食乙醇饮酒改变了乙醇饮用模式并抑制纹状体加巴能传播（Wilcox等，Neuropsychopharmacology 2014） 大多数小鼠菌株表现出的低水平自愿性乙醇消耗的限制了对重和暴饮暴食的神经生物学的研究（Crabbe等，2011）。最近，已经显示出一种间歇性进入乙醇的模型引起小鼠的暴饮暴食和与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的饮酒，利用小鼠的昼夜节律模式在两个小时的饮酒中可靠地消费。 C57BL/6J小鼠的BEC达到高于80 mg/dl的BEC，并显示出诸如运动障碍之类的中毒迹象（Rhodes等，2007）。 DID是一个强大的范式，已成功地用于研究调节暴饮暴食样乙醇消耗的神经元电路和信号（Sprow，2012）。尽管这种间歇性访问模型取得了成功，但尚未完全了解获得自愿乙醇饮用的机制。在这项研究中，我们在实验室中建立了DIC，并表明它会产生自愿乙醇摄入和血液乙醇浓度的可靠升级。我们表征了小鼠的饮用模式，并使用舔仪间歇性地进入乙醇，以在数周的自愿性乙醇消耗中记录每次次回合，并分析了纹状体神经元的突触形态，并分析了最后一个乙醇狂饮后的2天和30天。结果代表了对酒精场的新颖而重要的贡献，因为它们确定了瓶装交换，这是DID的组成部分，这是一种可能的机制，通过这种机制，间歇性通道通过诱导小鼠以较高的速度饮酒来促进获得自愿性乙醇饮酒行为。 随着时间的流逝，老鼠会改变其乙醇饮用方式，并在每次会议开始时提高饮酒速度。 更快的乙醇饮用与较高的BEC相关，并且在治疗6周后观察到了对乙醇的偏爱。有趣的是，在纹状体或伏脊柱密度中均未检测到任何变化，并且仅暂时看到脊柱长度的缩短，这表明这些行为变化发生在大脑突触形态的长期变化中。