Neural Actions of Toluene

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和未充分研究的健康问题。这些制剂也被称为滥用吸入剂，因其致醉作用而被自愿吸入或“吸入”，其使用在儿童和青少年中特别普遍。挥发性溶剂是法律的，存在于各种家用和商用产品中，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反应有关，包括社会和学术表现下降、大脑异常和溶剂诱导的心律失常导致的猝死综合征。虽然滥用吸入剂会产生类似乙醇的中毒症状，但这些作用的基础部位和作用机制在很大程度上尚不清楚。在NIDA资助下进行的研究重点是确定挥发性溶剂的作用部位和机制，以及这些化合物如何影响与成瘾有关的大脑区域。在该项目资助的最初阶段，我们生成的数据显示，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令人惊讶的选择性。这些发现清楚地表明，滥用的吸入剂（如甲苯）对介导各种滥用药物作用的通道具有重要和特定的作用。在目前的资助期间，我们研究了甲苯对成瘾神经回路中神经元的影响，包括内侧前额叶皮层和腹侧被盖区的神经元。这些研究的结果表明，甲苯通过对离子型GluRs的直接作用和通过新型内源性大麻素介导的信号转导抑制来减少mPFC神经元中的多巴胺能EPSC。我们还发现，短暂暴露于甲苯蒸气的青春期动物强烈增强了中脑边缘DA神经元中的AMPA/NMDA比率，而对投射到前额皮质的神经元几乎没有影响。此外，DA神经元兴奋性的这些变化依赖于前额叶皮层的输出，这表明该区域在调节滥用吸入剂的奖励效应中起着重要作用。在这个应用程序中，我们提出了三个具体的目标来扩展这些令人兴奋的发现。目的1将确定如何急性甲苯影响中棘神经元的功能，在延髓核和DA神经元的腹侧被盖区，重点是内源性大麻素在介导这些行动的作用。目标2中的研究将检查甲苯作用对腹侧被盖区DA神经元兴奋性的年龄依赖性，以及青春期短暂暴露于甲苯蒸气如何影响成年动物的神经元功能和行为。目的3将验证以下假设：腹侧被盖区DA神经元兴奋性的mPFC依赖性调节是内源性大麻素依赖性的，并且研究将绘制mPFC和腹侧被盖区之间的神经回路，以明确建立这些作用的机制。总的来说，这些研究的结果将填补我们关于滥用吸入剂对成瘾神经回路的作用的知识中的一个重要空白。

DESCRIPTION (provided by applicant): 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 can 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 has focused on defining the sites and mechanisms of action of volatile solvents and how these compounds affect brain areas involved in addiction. During the initial period of funding of this project, we generated data that 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. These findings clearly 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. During the current funding period, we examined the effects of toluene on neurons within the addiction neurocircuitry including those in the medial prefrontal cortex and ventral tegmental area. Results from these studies show that toluene reduces glutamatergic EPSCs in mPFC neurons via both direct actions on ionotropic GluRs and via a novel endocannabinoid mediated depression of signaling. We also showed that 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, these 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. In this application, we propose three specific aims to extend these exciting findings. Aim 1 will determine how acute toluene affects the function of medium spiny neurons in the nucleus accumbens and DA neurons in the VTA with a focus on the role of endocannabinoids in mediating these actions. Studies in Aim 2 will examine the age-dependence of toluene action on VTA DA neuron excitability and how brief exposures to toluene vapor during adolescence affects neuronal function and behavior in the adult animal. Aim 3 will test the hypothesis that the mPFC dependent regulation of VTA DA neuron excitability is endocannabinoid dependent and studies will map the neurocircuitry beween mPFC and VTA to clearly establish a mechanism for these effects. Overall, results from these studies will fill an important gap in our knowledge regarding the actions of abused inhalants on the addiction neurocircuitry.