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、未被充分研究的健康问题。这些药物也被称为滥用吸入剂，因其醉人效果而被自愿吸入或“吸入”，它们的使用在儿童和青少年中尤其普遍。挥发性溶剂是合法的，存在于各种家用和商业产品中，包括胶水、粘合剂和油漆稀释剂。接触这些化合物与各种不良反应有关，包括社交和学习成绩下降、大脑异常以及由溶剂引起的心律失常引起的猝死综合征。尽管滥用吸入剂会产生类似酒精的中毒迹象，但这些影响背后的作用部位和作用机制在很大程度上尚不清楚。这项由NIDA资助的研究重点是确定挥发性溶剂的作用部位和作用机制，以及这些化合物如何影响与成瘾有关的大脑区域。在这个项目资助的最初阶段，我们产生的数据显示，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惊人的选择性。这些研究结果清楚地证明，甲苯等被滥用的吸入剂在调解各种滥用药物的作用的渠道上具有重要和具体的作用。在目前的资助期间，我们研究了甲苯对成瘾神经回路中的神经元的影响，包括内侧前额叶皮质和腹侧被盖区的神经元。这些研究的结果表明，甲苯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来减少mPFC神经元中的谷氨酸能EPSCs。我们还发现，青少年动物短暂暴露于甲苯蒸气可显著提高中脑边缘DA神经元的AMPA/NMDA比率，而对投射到前额叶皮质的神经元影响不大。此外，DA神经元兴奋性的这些变化依赖于前额叶皮质的输出，这表明该区域在调节滥用吸入剂的奖赏效应中发挥着重要作用。在这项申请中，我们提出了三个具体目标来扩展这些令人兴奋的发现。目的1研究急性甲苯对伏核中棘神经元和伏隔核DA神经元功能的影响，重点探讨内源性大麻素在这些作用中的作用。目标2的研究将考察甲苯对VTA 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汽如何影响成年动物的神经元功能和行为。目的3验证mPFC对VTA DA神经元兴奋性的调节是内源性大麻素依赖性的假说，研究将绘制mPFC和VTA之间的神经回路图，以明确建立这些影响的机制。总体而言，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.