Neural Actions of Toluene

项目摘要 使用挥发性有机溶剂作为滥用药物是一个重大的、尚未得到充分研究的健康问题。这些 药物，也被称为滥用吸入剂，由于其醉人效应和他们的 在儿童和青少年中，使用情况尤其普遍。挥发性溶剂是合法的，可以在 各种家用和商用产品，包括胶水、粘合剂和油漆稀释剂。暴露于 这些化合物与各种不良影响有关，从减少社会和学术 表现、脑异常和溶剂性心脏病所致的猝死综合征 心律不齐。虽然滥用吸入剂会产生类似酒精的中毒迹象，但其部位和机制 这些影响背后的行动在很大程度上是未知的。在NIDA资助的这笔资金下进行的研究 确定滥用吸入剂，如甲苯，对所涉及的渠道有重要和特定的作用 在调解各种滥用毒品的行为时。此外，我们已经证明，甲苯可以减少 MPFC神经元中的谷氨酸能EPSCs通过直接作用于离子型GluR和通过一种新的 内源性大麻素介导的信号抑制。幼年动物对甲苯蒸气的短暂暴露 显著提高中脑边缘多巴胺能神经元的AMPA/NMDA比值，而对 投射到前额叶皮质。此外，DA神经元兴奋性的变化依赖于输出 前额叶皮质提示该区域在调节虐待的奖赏效应中起重要作用 吸入剂。最近的研究结果表明，急性接触甲苯会引起mPFC神经元活性的变化。 在重复曝光时，随子区域、层、投影目标和曝光年龄的不同而变化 诱导与mPFC-NAC信号选择性改变相关的条件性位置偏爱。倒车 这些化学发生途径的改变阻断了CPP的表达。在此续签申请中， 我们提出了三个具体目标来进一步扩展这些令人兴奋的发现，并研究了NAC神经元的作用 作为甲苯的奖励。目标1将确定暴露在甲苯蒸汽中如何影响兴奋性和突触 伏核中棘神经元(MSN)的体内外信号传递 接近了。目标2的研究将开发和使用一种新的甲苯蒸汽自我给药模型 检查自愿甲苯暴露对NAC MSN生理的影响。目标3将检验这一假设 通过控制NAC-MSN的活性及其特异性来阻断甲苯蒸气的自我给药 来自mPFC亚区的兴奋性输入。总体而言，这些研究的结果将填补 我们对滥用吸入剂对成瘾神经回路的作用的了解。

Project Summary The use of volatile organic solvents as drugs of abuse is a significant and understudied health problem. These agents, also termed abused inhalants, are voluntarily inhaled or “huffed” for their intoxicating effects and their use is especially prevalent among children and adolescents. Volatile solvents are legal and are found in a wide variety of household and commercial products including glues, adhesives and paint thinners. Exposure to these compounds is associated with a variety of adverse effects ranging from reduced social and academic performance, brain abnormalities and a sudden-death syndrome resulting from solvent-induced cardiac arrhythmia. Although abused inhalants produce ethanol-like signs of intoxication, the sites and mechanisms of action that underlie these effects are largely unknown. Research carried out under this NIDA funded grant established that abused inhalants such as toluene have important and specific actions on channels implicated in mediating the actions of a wide variety of drugs of abuse. In addition, we have shown that toluene reduces glutamatergic EPSCs in mPFC neurons via both direct actions on ionotropic GluRs and via a novel endocannabinoid mediated depression of signaling. A brief exposure of adolescent animals to toluene vapor robustly enhances the AMPA/NMDA ratio in mesolimbic DA neurons while having little effect on those that project to the prefrontal cortex. Moreover, the changes in DA neuron excitability were dependent on the output of prefrontal cortex suggesting an important role for this region in regulating the rewarding effects of abused inhalants. Recent results show that an acute exposure to toluene produces changes in mPFC neuron activity that vary depending on the sub-region, layer, projection target and age at exposure while repeated exposures induce a conditioned place preference associated with selective alterations in mPFC-NAc signaling. Reversing these alterations with chemogenetic approaches blocked the expression of CPP. In this renewal application, we propose three specific aims to further extend these exciting findings and examine the role of NAc neurons in toluene reward. Aim 1 will determine how exposure to toluene vapor affects the excitability and synaptic signaling of medium spiny neurons (MSNs) in the nucleus accumbens using both in vitro and in vivo approaches. Studies in Aim 2 will develop and use a novel model of toluene vapor self-administration to examine effects of voluntary toluene exposure on NAc MSN physiology. Aim 3 will test the hypothesis that self-administration of toluene vapor is blocked by manipulating the activity of NAc MSNs and their specific excitatory inputs from mPFC sub-regions. Overall, the results from these studies will fill an important gap in our knowledge regarding the actions of abused inhalants on the addiction neurocircuitry.