Neuroplasticity Associated with Acute Toluene Inhalation

描述(申请人提供)：挥发性有机溶剂是滥用吸入剂药物类别的一部分，是在常见的家用产品中发现的化合物，如油漆、油漆稀释剂、油漆和胶水。在儿童和青少年中，使用这些制剂使人醉酒的现象尤为普遍。吸入剂滥用可能会产生严重的不良后果，如认知障碍、大脑异常、器官损伤，甚至因吸入剂引起的心律失常而猝死。甲苯是一种典型的滥用吸入剂，它抑制NMDA介导的电流，并对GABA突触传递具有兴奋作用等作用。来自啮齿动物行为研究的证据表明，甲苯具有积极的增强作用，类似于其他滥用药物。在负责编码刺激突显的腹侧被盖区(VTA)，甲苯增加了多巴胺(DA)细胞的放电，暴露于甲苯的滥用水平导致伏隔核(NAC)和内侧前额叶皮质(MPFC)细胞外DA的增加。对这一建议的初步研究表明，体外应用甲苯可诱导mPFC锥体神经元的长期抑制(LTD)。总而言之，这些发现表明，甲苯暴露影响了负责奖励(VTA：NAC)和认知(MPFC)的大脑区域。这项建议通过检测急性体内甲苯暴露对神经可塑性标记物的影响来扩展这些发现。目的1利用全细胞膜片钳电生理学和急性脑片研究急性甲苯蒸气暴露是否能诱导大鼠大脑中脑皮质锥体细胞和VTA DA神经元兴奋性突触的持续性生理性改变。目的研究急性甲苯暴露是否会引起mPFC和VTA结构可塑性标记物的长期变化，方法是用Diolistic细胞标记法和分析树突棘。这些实验的结果将有助于确定甲苯滥用潜力的神经底物。 与公共卫生相关：美国约16%的8年级学生曾使用吸入剂中毒，对于许多首次吸毒者来说，第一次吸毒经历是滥用吸入剂。从这项提案中包含的实验中收集的数据将提供对甲苯的机制的洞察。甲苯是一种在胶水、漆器和喷漆中发现的典型吸入剂，它如何利用大脑奖励和认知系统。这些结果将澄清使用甲苯和类似吸入剂的危险，从而最终可以改进教育和预防战略。

DESCRIPTION (provided by applicant): Volatile organic solvents, part of the abused inhalants drug class, are compounds found in common household products, such as paints, paint thinners, lacquers and glues. The use of these agents for intoxicating purposes is particularly prevalent among children and adolescents. Inhalant abuse can have profound adverse consequences, such as cognitive impairment, brain abnormalities, organ damage, and even sudden death, a result of inhalant-induced cardiac dysrhythmia. Toluene, a prototypical abused inhalant, inhibits NMDA mediated currents and has an excitatory effect on GABA synaptic transmission, among other effects. Evidence from rodent behavioral studies indicates that toluene has positive-reinforcing properties, similar to other drugs of abuse. In the ventral tegmental area (VTA), a region responsible for encoding the salience of stimuli, toluene increases dopaminergic (DA) cell firing, and exposure to abuse levels of toluene induces an increase in extracellular DA in the nucleus accumbens (NAc) and medial prefrontal cortex (mPFC). Preliminary studies for this proposal suggest that toluene applied in vitro induces long-term depression (LTD) in mPFC pyramidal neurons. Together, these findings indicate that toluene exposure impacts regions of the brain responsible for reward (VTA:NAc) and cognition (mPFC). This proposal extends these findings by examining the effect of acute in vivo toluene exposure on markers of neuroplasticity. Aim 1 will use whole-cell patch clamp electrophysiology and acute brain slices to determine whether acute toluene vapor exposure induces persistent physiological alterations in excitatory synapses of mPFC pyramidal neurons and VTA DA neurons. Aim 2 will determine whether acute toluene exposure induces long-term changes in markers of structural plasticity in the mPFC and VTA by using the diolistic cell labeling method and analyzing dendritic spines. Results from these experiments will help determine the neurological substrates of toluene's abuse potential. PUBLIC HEALTH RELEVANCE: About 16% of 8th grade students in the US have used inhalants to get intoxicated and for many first-time drug users, the first drug experience is an abused inhalant. Data collected from experiments contained in this proposal will provide insight into the mechanisms of how toluene, a prototypical inhalant found in glues, lacquers and spray paints, can co-opt brain reward and cognitive systems. These results will clarify the danger of using toluene and similar inhalants so that ultimately education and prevention strategies can be improved.