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.

由腹侧盖（VTA）区域以及投射到伏隔核（ACB）引起的多巴胺能神经元是脑电路的关键要素，可唤醒，动机和增强。在这种中室途径中，多巴胺神经传递的增加与精神刺激剂，酒精和其他滥用药物的增强作用有关。 先前的研究表明，甲苯吸入会在动物模型中产生增强作用，并被人类滥用。尽管在ACB中尚未报道大鼠对甲苯的急性暴露在背纹状体中增加多巴胺的释放。这些发现导致了以下假设：多巴胺独立的机制介导了甲苯和其他吸入剂的滥用责任。但是，解剖学研究表明，ACB由两个称为壳和核心的子区域组成。据报道，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。 我们进行了一系列研究，以确定甲苯对VTA和ACB中神经元活性的特异性影响。现在，使用体外电生理学，我们已经表明，在行为相关的甲苯浓度直接刺激VTA中的多巴胺神经元，但在周围的中脑区域中不直接刺激多巴胺神经元。当突触传播减少时，对VTA神经元的甲苯刺激持续存在。此外，与含有神经元的非多巴胺不同，VTA多巴胺神经元发射的大小不会在旨在模仿“ huffing”的更长暴露期间下降。使用双探针体内微透析来监测多巴胺的释放，我们表明甲苯直接在VTA中灌注会增加VTA中的多巴胺浓度（Somatendendritic释放）及其末端投影位点及其末端投影位点ACB。多巴胺对甲苯反应的大小也随评估VTA子区域的函数而变化。这些结果提供了第一个证明，即使对甲苯的短暂暴露也会增加动作势驱动到中腔VTA多巴胺神经元，从而增强了ACB中的多巴胺传播。甲苯通过直接激活VTA多巴胺神经元（独立于透射输入独立于跨突触输入）来刺激中核神经传递的发现提供了对神经底物的见解，这些神经底物可能有助于甲苯滥用的起始和病理生理学。 重要的是，他们认为中层途径可能有助于滥用甲苯和其他吸入剂，而瞄准该系统可能有助于治疗甲苯滥用。 高剂量酒精的反复使用会导致记忆和认知中的缺陷。这些作用至少部分归因于海马功能的酒精引起的改变和该区域神经元的丧失。 Kappa阿片受体（KOPR）和内源性KOPR配体的Dynorphin富含海马，并在调节海马神经元活性方面起重要功能。我们的合作者（NIH和Karolinska研究生教育中的合作计划）获得了证据，表明在人类酒精的海马中，dynorphin的组织水平以及Prodynorphin（Prodynorphin（Prodynorphin）的表达升高。相比之下，其他阿片类肽系统是不变的。 KOPR位于海马中的谷氨酸能神经元上，调节谷氨酸释放。谷氨酸和多啡肽都与长期抑郁症（LTD）的调节有关，这是一种突触可塑性的一种形式，对学习很重要。然而，重要的是，过量的谷氨酸对神经元有毒，可能会损害学习和记忆。 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海马的CA3区域内的谷氨酸传播。我们使用了一种口服烤模型，该模型能够提供高剂量酒精，但与通常用于诱导酒精依赖性的酒精吸入模型相关的副作用无关。我们的研究表明，每天的酒精（40％V/V ETOH：10 mL/kg）烤会产生学习和记忆中依赖性和缺陷的体征。 使用莫里斯水迷宫的研究表明，在停止重复，暴饮暴食后，对Kopr拮抗剂的全身性施用会阻止酒精产生的记忆缺陷。观察到类似的效应，以应对CA3区域的Kopr的选择性阻断，表明该区域的Kopr封锁足以防止酒精的神经毒性作用。使用常规和定量的微透析（请参阅Chefer等，2007，有关综述），我们发现酒精引起的记忆障碍与CA3中的基底和去极化诱发的谷氨酸释放的增加有关，并且这些神经化学的变化是通过对A a a a剂的给药来预防的。血液酒精浓度不受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。 正在进行的研究正在确定饮酒产生的谷氨酸传播的改变是由于对谷氨酸能神经元的直接影响而产生的。 GABA释放的变化反过来又调节海马中的兴奋性传播或激活细胞死亡级联反应。这些研究的结果将使划定Kopr/Dynorphin系统激活有助于酒精诱发的神经毒性的机制。