Neuroplasticity Associated with Acute Toluene Inhalation

描述（由申请人提供）：挥发性有机溶剂，属于滥用吸入类药物的一部分，是在常见家用产品中发现的化合物，如油漆、油漆稀释剂、漆和胶水。以麻醉为目的使用这些药物在儿童和青少年中特别普遍。吸入剂滥用会产生严重的不良后果，如认知障碍、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，可抑制NMDA介导的电流，并对GABA突触传递具有兴奋作用。来自啮齿动物行为研究的证据表明，甲苯具有积极强化的特性，类似于其他滥用药物。在腹侧被皮层（VTA），一个负责编码刺激显著性的区域，甲苯增加了多巴胺能（DA）细胞的放电，暴露于滥用水平的甲苯诱导伏隔核（NAc）和内侧前额叶皮层（mPFC）的细胞外DA增加。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）。总之，这些发现表明，甲苯暴露会影响大脑中负责奖励（VTA:NAc）和认知（mPFC）的区域。本研究通过研究急性体内甲苯暴露对神经可塑性标志物的影响，扩展了这些发现。目的1将使用全细胞膜片钳电生理学和急性脑切片来确定急性甲苯蒸气暴露是否会引起mPFC锥体神经元和VTA DA神经元兴奋性突触的持续生理改变。目的2将通过使用diolistic cell标记方法和分析树突棘来确定急性甲苯暴露是否会导致mPFC和VTA结构可塑性标志物的长期变化。这些实验的结果将有助于确定甲苯滥用潜力的神经学基础。

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.