Neural Actions of Toluene

甲苯的神经作用

• 批准号: 8016608
• 负责人: JOHN J. WOODWARD
• 金额: $ 31.37万
• 依托单位: MEDICAL UNIVERSITY OF SOUTH CAROLINA
• 依托单位国家: 美国
• 财政年份: 2002
• 资助国家: 美国
• 起止时间: 2002-04-15 至 2013-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8016608
• 关键词: Action Potentials; Acute; Adhesives; Adolescent; Adverse effects; Area; Arrhythmia; Attention; Behavior; Behavior Control; Brain; Brain region; Breathing; Cells; Child; Coculture Techniques; Complex; Detection; Electrophysiology (science); Elements; Ethanol; Exposure to; Frequencies; Funding; Gated Ion Channel; Glues; Glutamates; Health; Household; Impairment; In Vitro; Interneurons; Intoxication; Ion Channel; Knowledge; Legal; Ligands; Link; Maintenance; Measures; Mediating; Mediator of activation protein; Membrane; Molecular; Motor output; N-Methyl-D-Aspartate Receptors; N-Methylaspartate; NMDA receptor 2B; NR1 gene; NR2B NMDA receptor; Neurons; Nicotinic Receptors; Nucleus Accumbens; Organic solvent product; Paint; Pathway interactions; Pattern; Performance; Pharmaceutical Preparations; Play; Prefrontal Cortex; Property; Receptor Activation; Receptor Inhibition; Recombinants; Research; Rewards; Role; Shapes; Short-Term Memory; Signal Transduction; Site; Slice; Solvents; Specificity; Stimulus; Sudden Death; Synapses; Synaptic plasticity; Syndrome; System; Techniques; Testing; Toluene; Ventral Tegmental Area; addiction; cholinergic; dopaminergic neuron; drug of abuse; hippocampal pyramidal neuron; in vivo; inhalation drug abuse; knockout animal; neuronal excitability; neurotransmission; novel; patch clamp; prototype; receptor; receptor-mediated signaling; relating to nervous system; reward processing; transmission process; voltage

DESCRIPTION (provided by applicant): The use of volatile organic solvents as drugs of abuse is an important health problem. These agents, often termed abused inhalants, are voluntarily inhaled or "huffed" for their intoxicating effects. The use of abused inhalants is especially prevalent among children and adolescents since these compounds are legal and are found in a wide variety of household and commercial products including glues, adhesives and paint thinners. Abused inhalants are associated with a variety of adverse effects ranging from reduced academic performance, brain abnormalities and a sudden-death syndrome resulting from solvent-induced cardiac arrhythmia. Although abused inhalants produce ethanol-like signs of intoxication, their sites and mechanisms of action that underlie these effects are largely unknown. Research carried out during the previous funding period of this project used recombinant expression techniques and electrophysiology to study the effects of abused inhalants on ion channels widely expressed by brain neurons. Results from these studies revealed a surprising degree of selectivity for the effects of abused inhalants on both voltage-gated and ligand-gated ion channels that regulate neuronal excitability. In particular, the NR1/2B NMDA receptors and the 1422 nicotinic acetylcholine receptor were among the most sensitive channels identified. In this application, we focus on the role that these channels play in mediating the effects of toluene, the prototype abused inhalant, on the activity of principal neurons within three brain regions known to be important in mediating the effects of drugs of abuse. Whole-cell patch-clamp electrophysiology will be used to study the effects of toluene on dopamine neurons of the ventral tegmental area (VTA), medium spiny neurons of the nucleus accumbens (NAcc) and deep-layer pyramidal neurons of the prefrontal cortex (PFC). Aim 1 will determine the toluene sensitivity of NMDA EPSCs within the addiction neurocircuitry with a special focus on NR1/2B receptors. Aim 2 will determine the effect of acute toluene on VTA DA neuron excitability with a special focus on 1422 nAchRs. Aim 3 will use a novel triple-slice co-culture system to determine the effects of toluene on NR1/2B and 1422 nAchRs that mediate complex firing patterns produced by PFC neurons. Finally, Aim 4 will test the hypothesis that exposure to toluene in vivo induces changes in indicators of plasticity in glutamatergic synapses measured in vitro. Results from these studies will fill an important gap in our knowledge and will define the actions of toluene on key elements of the addiction neurocircuitry. PUBLIC HEALTH RELEVANCE Abused inhalants are an important class of drugs of abuse that have received relatively little attention with respect to their mechanisms of action. Research to be carried out in this proposal will provide a detailed analysis of the effects of abused inhalants on neurons within brain areas involved in addiction.

描述（由申请人提供）：使用挥发性有机溶剂作为滥用药物是一个重要的健康问题。这些经常被称为滥用吸入剂的药物是自愿吸入或“烦恼”的，因为它们的醉酒作用。在儿童和青少年中，由于这些化合物是合法的，并且在各种各样的家庭和商业产品中发现，包括胶水，粘合剂和油漆稀释剂，因此在儿童和青少年中使用滥用吸入剂尤为普遍。滥用的吸入剂与各种不良反应有关，包括降低的学业表现，脑异常和因溶剂引起的心律失常引起的突然死亡综合征。尽管被滥用的吸入剂产生了类似乙醇的中毒迹象，但其位置和作用机制的基础是这些作用的基本未知。在该项目的前一个资金期间进行的研究使用重组表达技术和电生理学来研究滥用吸入剂对脑神经元广泛表达的离子通道的影响。这些研究的结果表明，滥用吸入剂对调节神经元兴奋性的电压门控和配体门控离子通道的影响具有惊人的选择性。特别是，NR1/2B NMDA受体和1422个烟碱乙酰胆碱受体是最敏感的通道之一。在此应用中，我们着重于这些渠道在介导甲苯（滥用原型的原型吸入剂）的影响中对主要神经元在三个大脑区域中的活性的作用，该作用在介导滥用药物的影响方面很重要。全细胞斑块钳电生理学将用于研究甲苯对腹侧段区域多巴胺神经元（VTA），伏隔核（NACC）（NACC）的中刺神经元的影响和前额叶皮质（PFC）的深层金字塔神经元。 AIM 1将确定成瘾神经记录中NMDA EPSC的甲苯敏感性，特别关注NR1/2B受体。 AIM 2将确定急性甲苯对VTA DA神经元兴奋性的影响，并特别关注1422 NACHRS。 AIM 3将使用一种新型的三片共培养系统来确定甲苯对NR1/2B和1422 NACHR的影响，从而介导PFC神经元产生的复杂发射模式。最后，AIM 4将检验以下假设：在体内暴露于体内的甲苯会导致体外测量的谷氨酸能突触中可塑性的变化。这些研究的结果将填补我们知识的重要空白，并将定义甲苯对成瘾神经记录关键要素的作用。公共卫生相关性滥用吸入剂是一类重要的虐待药物，在其行动机制方面，人们的关注相对较少。该提案中要进行的研究将详细分析被滥用的吸入剂对成瘾涉及的大脑区域内神经元的影响。