Effect Of Drugs of Abuse On Synaptic Transmission In Nucleus Accumbens

滥用药物对伏核突触传递的影响

• 批准号: 8148510
• 负责人: Carl R. Lupica
• 金额: $ 36.35万
• 依托单位: NATIONAL INSTITUTE ON DRUG ABUSE
• 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/8148510
• 关键词: Address; Affect; Behavioral; CNR2 gene; Development; Dopamine; Drug Addiction; Drug abuse; Extramural Activities; Glutamates; Goals; Green Fluorescent Proteins; Learning; Light; Marijuana; Monitor; Moods; Motivation; Mus; Nucleus Accumbens; Opioid; Output; Pharmaceutical Preparations; Preparation; Process; Site; Slice; Synaptic Transmission; Transgenic Mice; drug of abuse; nerve supply; transmission process

The nucleus accumbens (NAc) represents a critical site for the rewarding and addictive properties of several classes of abused drugs. Therefore, it is necessary to understand the actions of abused drugs such as marijuana, cocaine, and opioids on physiology of this system. In addition, this brain nucleus is known to mediate motivational aspects of behavior. For this reason it has been implicated in a variety of psychiatric disorders that involve alterations in mood and motivation, as well as in the process of drug addiction. The NAc medium spiny GABAergic output neurons (MSNs) receive innervation from other intrinsic MSNs, and glutamatergic innervation from extrinsic sources. Both GABAergic and glutamatergic synapses onto MSNs are inhibited by abused drugs, suggesting that this action may contribute to their rewarding properties. In addition, abused drugs are known to increase NAc dopamine (DA). One role of DA in regulating NAc activity may be to contribute to the long-term changes in excitatory transmission observed following repetitive activation of glutamatergic afferents. However, the precise mechanisms through which such synaptic plasticity develops, and how drugs of abuse, including cannabinoids (CBs), alter such synaptic plasticity, remain poorly understood. To investigate the actions of CBs in the NAc, we are utilizing both electrophysiological and fast scan cyclic voltammetry (FSCV) recording techniques in brain slices. By combining these approaches, we hope to be able to simultaneously monitor changes in DA levels and the development of synaptic plasticity. We are also collaborating with Dr. Bruce Hope investigating the effects of repeated cocaine treatment on synaptic inputs to MSNs. To do this, we are using mice that express green fluorescent protein in only MSNs that are activated during cocaine sensitization. By visualizing these specific neurons in our slice preparation, we can perform electrophysiological recordings from these cells and assess the mechanisms supporting cocaine sensitization. We have also recently investigated the consequences of cannabinoid CB1 receptor deletion in transgenic mice on DA release in the NAc and on locomotor behavior elicited by cocaine. These studies address the role of the NAc in motivated behavior, and the interaction between cannabinoid and DA systems in the NAc. More recently we have begun to assess the potential role of cannabinoid CB2 receptors in the nucleus accumbens to shed light on intriguing behavioral experiments in which these receptors are proposed to play an important role in reward processes. Since the NAc is involved in mediating all motivated behavior these studies should delineate neurochemical systems involved in motivation and learning behavior.

丘脑核（NAc）代表了几类滥用药物的奖励和成瘾特性的关键部位。因此，有必要了解滥用药物，如大麻，可卡因和阿片类药物对该系统的生理作用。此外，这个脑核团被认为是行为动机方面的中介。 由于这个原因，它与各种精神疾病有关，这些精神疾病涉及情绪和动机的改变，以及药物成瘾的过程。 NAc中型棘状GABA能输出神经元（MSN）接受来自其他内在MSN的神经支配，以及来自外在来源的GABA能神经支配。MSNs上的GABA能和多巴胺能突触都受到滥用药物的抑制，这表明这种作用可能有助于它们的奖励特性。 此外，已知滥用药物会增加NAc多巴胺（DA）。 DA在调节NAc活性中的一个作用可能是促进兴奋性传递的长期变化，这些变化在重复激活多巴胺能传入后观察到。 然而，这种突触可塑性发展的确切机制，以及滥用药物（包括大麻素（CB））如何改变这种突触可塑性，仍然知之甚少。 为了研究CBs在NAc中的作用，我们在脑切片中利用电生理和快速扫描循环伏安法（FSCV）记录技术。 通过结合这些方法，我们希望能够同时监测DA水平的变化和突触可塑性的发展。 我们还与布鲁斯霍普博士合作，研究重复可卡因治疗对MSN突触输入的影响。 为了做到这一点，我们使用的小鼠只在可卡因致敏过程中激活的MSN中表达绿色荧光蛋白。 通过在我们的切片制备中可视化这些特定的神经元，我们可以从这些细胞中进行电生理记录，并评估支持可卡因致敏的机制。 我们最近还研究了转基因小鼠中大麻素CB1受体缺失对NAc中DA释放和可卡因引起的运动行为的影响。 这些研究解决了NAc在动机行为中的作用，以及NAc中大麻素和DA系统之间的相互作用。 最近，我们已经开始评估大麻素CB2受体在神经核中的潜在作用，以揭示有趣的行为实验，其中这些受体被认为在奖励过程中发挥重要作用。 由于NAc参与调节所有动机性行为，这些研究应该描述参与动机和学习行为的神经化学系统。