Neurobiology of Alcohol and Inhalant Abuse

酒精和吸入滥用的神经生物学

• 批准号: 7733833
• 负责人: Toni Shippenberg
• 金额: $ 60.88万
• 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/7733833
• 关键词: Action Potentials; Acute; Adverse effects; Affect; Alcohol abuse; Alcohol consumption; Alcohol dependence; Alcohols; Animal Model; Animals; Arousal; Attenuated; Blood alcohol level measurement; Brain; Breathing; Cell Death; Cognition; Corpus striatum structure; Daily; Dependence; Dopamine; Dorsal; Dose; Drug Kinetics; Drug usage; Dynorphins; Electrophysiology (science); Elements; Ethanol; Exposure to; Fire - disasters; Functional disorder; Genes; Glues; Glutamates; Health; Heterogeneity; Hippocampus (Brain); Human; Impaired cognition; In Vitro; Inhalant dose form; Institutes; Learning; Ligands; Long-Term Depression; Mediating; Memory; Memory impairment; Microdialysis; Midbrain structure; Modeling; Monitor; Motivation; Neurobiology; Neurologic; Neurons; Nucleus Accumbens; Opioid; Opioid Peptide; Oral; Paint; Pathway interactions; Pattern; Perfusion; Pharmaceutical Preparations; Pharmacological Treatment; Property; Psychological reinforcement; Psychotropic Drugs; Rattus; Reporting; Role; Sampling; Series; Short-Term Memory; Site; Synaptic Transmission; Synaptic plasticity; System; Techniques; Teenagers; Tissues; Toluene; Transcriptional Activation; United States National Institutes of Health; Up-Regulation; Ventral Tegmental Area; alcohol and other drug; alcohol effect; behavior test; design; dopaminergic neuron; drug of abuse; gamma-Aminobutyric Acid; in vivo; inhalation drug abuse; insight; kappa opioid receptors; loss of function; morris water maze; neurochemistry; neuromechanism; neuron loss; neurotoxic; neurotoxicity; neurotransmission; neurotransmitter uptake; postgraduate education; prevent; problem drinker; prodynorphin; programs; protective effect; psychostimulant; relating to nervous system; response; transmission process

Dopaminergic neurons arising from the ventral tegmental (VTA) area and projecting to the nucleus accumbens (ACb)are key elements of brain circuits that subserve arousal, motivation, and reinforcement. Increased dopamine neurotransmission within this mesoaccumbal pathway are implicated in the reinforcing effects of psychostimulants, alcohol, and other drugs of abuse. Previous studies have shown toluene inhalation produces reinforcing effects in animal models and is abused by humans. Although acute exposure of rats to toluene increases dopamine release in the dorsal striatum similar effects have not been reported in the ACb. These findings have led to the hypothesis that a dopamine-independent mechanism mediates the abuse liability of toluene and other inhalants. Anatomical studies, however, have shown that the ACb consists of two sub-regions termed the shell and the core. Heterogeneity of the VTA and in the responsiveness of VTA dopamine neurons to several drugs of abuse has been reported. We conducted a series of studies to determine whether there are sub-region-specific effects of toluene on neuronal activity in the VTA and ACb. Using in-vitro electrophysiology, we have now shown that behaviorally relevant concentrations of toluene directly stimulates dopamine neurons in the VTA but not in surrounding midbrain regions. Toluene stimulation of VTA neurons persists when synaptic transmission is reduced. Moreover, unlike non-dopamine containing neurons, the magnitude of VTA dopamine neuron firing does not decline during longer exposures designed to emulate 'huffing'. Using dual-probe in-vivo microdialysis to monitor dopamine release, we show that perfusion of toluene directly into the VTA increases dopamine concentrations in the VTA (somatodendritic release) and its terminal projection site, the ACb. The magnitude of the dopamine response to toluene also varied as a function of the VTA sub-region evaluated. These results provide the first demonstration that even brief exposure to toluene increases action potential drive onto mesoaccumbal VTA dopamine neurons, thereby enhancing dopamine transmission in the ACb. The finding that toluene stimulates mesoaccumbal neurotransmission by activating VTA dopamine neurons directly (independently of transynaptic inputs) provide insights into the neural substrates that may contribute to the initiation and pathophysiology of toluene abuse. Importantly, they suggest that the mesoaccumbal pathway may contribute to the abuse of toluene and other inhalants and that targeting this system may be useful for the treatment of toluene abuse. The repeated use of high dose alcohol produces deficits in memory and cognition. These effects have been attributed, at least in part, to alcohol-evoked alterations in hippocampal function and loss of neurons in this region. Kappa opioid receptors (KOPr) and dynorphin, the endogenous KOPr ligand, are enriched in the hippocampus and serve an important function in regulating hippocampal neuronal activity. Our collaborators (NIH and Karolinska Institute Collaborative Program In Postgraduate Education)have obtained evidence that tissue levels of dynorphin, as well as the expression of prodynorphin, the gene encoding dynorphin, are elevated in the hippocampus of human alcoholics. In contrast, other opioid peptides systems are unaltered. KOPr is located on glutamatergic neurons in the hippocampus and modulates glutamate release. Both glutamate and dynorphin have been implicated in the modulation of long-term depression(LTD), a form of synaptic plasticity which is important for learning. Importantly, however, excess glutamate is toxic to neurons and can impair learning and memory. Given the role of the dynorphin/KOPr pathway in synaptic plasticity we have initiated studies to ascertain whether up-regulation of this opioid system contributes to deficits in cognition produced by alcohol and/or alcohol-evoked alterations in hippocampal neurochemistry, we intiated a series of studies to examine whether pharmacological treatments that block the activity of the KOPr/dynorphin system affect hippocampal-dependent memory and glutamate transmission within the CA3 region of the hippocampus. We have used an oral gavage model which enables delivery of high dose alcohol but is not associated with the side-effects associated with the alcohol inhalation model typically used to induced alcohol dependence. Our studies have shown that once daily alcohol (40% v/v ETOH: 10 ml/kg)gavage produces somatic signs of dependence and deficits in learning and memory. Studies using the Morris water maze have revealed that systemic adminsitration of KOPr antagonists following the cessation of repeated, binge alcohol administration prevent memory deficits produced by alcohol. Similar effects are observed in response to the selective blockade of KOPr in the CA3 region indicating that blockade of KOPr in this region is sufficient to prevent the neurotoxic effects of alcohol. Using conventional and quantitative microdialysis (see Chefer et al., 2007 for review), we have found that alcohol-evoked memory impairment is associated with increases in basal and depolarization-evoked glutamate release in CA3 and that these neurochemical changes are prevented by administration of a selective KOPr antagonist. Blood alcohol concentrations are unaffected by KOPr antagonists suggesting that a pharmacokinetic mechanisms underlies the protective effects of KOPr antagonist treatment. On-going studies are determining whether alterations in glutamate transmission produced by alcohol result from a direct effect on glutamatergic neurons; to changes in GABA release which, in turn, modulate excitatory transmission in the hippocampus or to activation of cell death cascades. Results from these studies will enable delineation of the mechanisms by which activation of the KOPr/dynorphin system contributes to alcohol-evoked neurotoxicity.

源自腹侧被盖 (VTA) 区域并投射到伏隔核 (ACb) 的多巴胺能神经元是促进唤醒、动机和强化的大脑回路的关键要素。中脑通路中多巴胺神经传递的增加与精神兴奋剂、酒精和其他滥用药物的增强作用有关。 先前的研究表明，吸入甲苯在动物模型中会产生强化作用，并被人类滥用。尽管大鼠急性暴露于甲苯会增加背侧纹状体中多巴胺的释放，但在 ACb 中尚未报道类似的效果。这些发现导致了这样的假设：不依赖多巴胺的机制介导了甲苯和其他吸入剂的滥用倾向。然而，解剖学研究表明 ACb 由两个子区域组成，称为壳和核。 VTA 的异质性以及 VTA 多巴胺神经元对几种滥用药物的反应性已有报道。 我们进行了一系列研究，以确定甲苯对 VTA 和 ACb 神经元活动是否存在亚区域特异性影响。利用体外电生理学，我们现在已经证明，行为相关浓度的甲苯会直接刺激 VTA 中的多巴胺神经元，但不会刺激周围的中脑区域。当突触传递减少时，甲苯对 VTA 神经元的刺激持续存在。此外，与不含多巴胺的神经元不同，VTA多巴胺神经元放电的强度在旨在模拟“呼气”的较长暴露期间不会下降。使用双探针体内微透析监测多巴胺释放，我们发现将甲苯直接灌注到 VTA 中会增加 VTA（体细胞树突释放）及其末端投射位点 ACb 中的多巴胺浓度。多巴胺对甲苯的反应强度也随着评估的 VTA 子区域的变化而变化。这些结果首次证明，即使短暂暴露于甲苯也会增加对中脑VTA多巴胺神经元的动作电位驱动，从而增强ACb中的多巴胺传递。甲苯通过直接激活 VTA 多巴胺神经元（独立于突触输入）来刺激中脑神经传递，这一发现为了解可能有助于甲苯滥用的引发和病理生理学的神经底物提供了见解。 重要的是，他们认为mesoaccumbal途径可能导致甲苯和其他吸入剂的滥用，并且针对该系统可能有助于治疗甲苯滥用。 反复使用高剂量酒精会导致记忆和认知缺陷。这些影响至少部分归因于酒精引起的海马功能改变和该区域神经元的丧失。 Kappa 阿片受体 (KOPr) 和强啡肽（内源性 KOPr 配体）在海马中丰富，在调节海马神经元活动中发挥重要作用。我们的合作者（美国国立卫生研究院和卡罗林斯卡学院研究生教育合作项目）获得的证据表明，人类酗酒者海马体中强啡肽的组织水平以及强啡肽原（编码强啡肽的基因）的表达升高。相比之下，其他阿片肽系统没有改变。 KOPr 位于海马体的谷氨酸能神经元上，调节谷氨酸的释放。谷氨酸和强啡肽都与长期抑郁（LTD）的调节有关，长期抑郁是一种对学习很重要的突触可塑性形式。然而，重要的是，过量的谷氨酸对神经元有毒，会损害学习和记忆。鉴于强啡肽/KOPr 通路在突触可塑性中的作用，我们启动了研究，以确定该阿片类药物系统的上调是否会导致酒精和/或酒精诱发的海马神经化学改变所产生的认知缺陷，我们启动了一系列研究研究阻断 KOPr/强啡肽系统活性的药物治疗是否会影响 CA3 内海马依赖性记忆和谷氨酸传输海马体区域。我们使用了口服强饲模型，该模型能够输送高剂量的酒精，但与通常用于诱发酒精依赖的酒精吸入模型相关的副作用无关。我们的研究表明，每天一次灌胃酒精（40％v/v 乙醇：10ml/kg）会产生依赖的躯体症状以及学习和记忆缺陷。 使用莫里斯水迷宫的研究表明，在停止反复酗酒后全身给予 KOPr 拮抗剂可以预防酒精引起的记忆缺陷。在 CA3 区域中选择性阻断 KOPr 也观察到类似的效果，表明在该区域阻断 KOPr 足以防止酒精的神经毒性作用。使用传统的定量微透析（参见Chefer等人，2007年综述），我们发现酒精引起的记忆障碍与CA3中基础谷氨酸和去极化引起的谷氨酸释放增加有关，并且这些神经化学变化可以通过施用选择性 KOPr 拮抗剂。血液中的酒精浓度不受 KOPr 拮抗剂的影响，这表明药代动力学机制是 KOPr 拮抗剂治疗的保护作用的基础。 正在进行的研究正在确定酒精引起的谷氨酸传输的改变是否是由于对谷氨酸能神经元的直接影响所致。 GABA 释放的变化进而调节海马的兴奋性传递或细胞死亡级联的激活。这些研究的结果将能够描述 KOPr/强啡肽系统的激活导致酒精引起的神经毒性的机制。

项目成果

The abused inhalant toluene increases dopamine release in the nucleus accumbens by directly stimulating ventral tegmental area neurons.

滥用的吸入甲苯通过直接刺激腹侧被盖区神经元来增加伏隔核中多巴胺的释放。

• 发表时间: 2007-07
• 作者: Riegel, Arthur C;Zapata, Agustin;Shippenberg, Toni S;French, Edward D
• 通讯作者: French, Edward D

Volatile anesthetics and endogenous cannabinoid anandamide have additive and independent inhibitory effects on alpha(7)-nicotinic acetylcholine receptor-mediated responses in Xenopus oocytes.

挥发性麻醉剂和内源性大麻素 anandamide 对非洲爪蟾卵母细胞中 α(7)-烟碱乙酰胆碱受体介导的反应具有累加和独立的抑制作用。

• 发表时间: 2008-03-17
• 作者: Jackson, Shelley N;Singhal, Sachin K;Woods, Amina S;Morales, Marisela;Shippenberg, Toni;Zhang, Li;Oz, Murat
• 通讯作者: Oz, Murat