Neuroplasticity Associated with Acute Toluene Inhalation

描述（由申请人提供）：挥发性有机溶剂是滥用吸入剂类药物的一部分，是常见家用产品中发现的化合物，如油漆、油漆稀释剂、清漆和胶水。儿童和青少年使用这些药剂致醉的情况特别普遍。吸入剂滥用可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导致的猝死。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。啮齿动物行为研究的证据表明，甲苯具有积极的强化特性，类似于其他滥用药物。在腹侧被盖区（VTA），一个负责编码刺激的显着性的区域，甲苯增加多巴胺能（DA）细胞放电，暴露于滥用水平的甲苯诱导增加细胞外DA在延髓核（NAc）和内侧前额叶皮层（mPFC）。初步研究表明，甲苯在体外诱导mPFC锥体神经元的长期抑制（LTD）。总之，这些研究结果表明，甲苯暴露影响大脑负责奖励（VTA：NAc）和认知（mPFC）的区域。该建议通过检查急性体内甲苯暴露对神经可塑性标志物的影响来扩展这些发现。目的1将使用全细胞膜片钳电生理学和急性脑切片，以确定是否急性甲苯蒸气暴露引起的mPFC锥体神经元和VTA DA神经元的兴奋性突触的持续生理改变。目的2将通过使用diolistic细胞标记方法和分析树突棘来确定急性甲苯暴露是否诱导mPFC和VTA中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.