Furlong Teri M, Duncan Jhodie R, Corbit Laura H, Rae Caroline D, Rowlands Benjamin D, Maher Anthony D, Nasrallah Fatima A, Milligan Carol J, Petrou Steven, Lawrence Andrew J, Balleine Bernard W
Brain & Mind Centre, University of Sydney, Sydney, New South Wales, Australia.
School of Psychology, University of Sydney, Sydney, New South Wales, Australia.
J Neurochem. 2016 Dec;139(5):806-822. doi: 10.1111/jnc.13858. Epub 2016 Nov 9.
Toluene is a commonly abused inhalant that is easily accessible to adolescents. Despite the increasing incidence of use, our understanding of its long-term impact remains limited. Here, we used a range of techniques to examine the acute and chronic effects of toluene exposure on glutameteric and GABAergic function, and on indices of psychological function in adult rats after adolescent exposure. Metabolomics conducted on cortical tissue established that acute exposure to toluene produces alterations in cellular metabolism indicative of a glutamatergic and GABAergic profile. Similarly, in vitro electrophysiology in Xenopus oocytes found that acute toluene exposure reduced NMDA receptor signalling. Finally, in an adolescent rodent model of chronic intermittent exposure to toluene (10 000 ppm), we found that, while toluene exposure did not affect initial learning, it induced a deficit in updating that learning when response-outcome relationships were reversed or degraded in an instrumental conditioning paradigm. There were also group differences when more effort was required to obtain the reward; toluene-exposed animals were less sensitive to progressive ratio schedules and to delayed discounting. These behavioural deficits were accompanied by changes in subunit expression of both NMDA and GABA receptors in adulthood, up to 10 weeks after the final exposure to toluene in the hippocampus, prefrontal cortex and ventromedial striatum; regions with recognized roles in behavioural flexibility and decision-making. Collectively, our data suggest that exposure to toluene is sufficient to induce adaptive changes in glutamatergic and GABAergic systems and in adaptive behaviour that may underlie the deficits observed following adolescent inhalant abuse, including susceptibility to further drug-use.
甲苯是一种常见的被滥用的吸入剂，青少年很容易接触到。尽管其使用发生率不断上升，但我们对其长期影响的了解仍然有限。在此，我们运用了一系列技术来研究青少年接触甲苯后，其对成年大鼠谷氨酸能和γ-氨基丁酸能功能以及心理功能指标的急性和慢性影响。对皮质组织进行的代谢组学分析表明，急性接触甲苯会导致细胞代谢改变，显示出谷氨酸能和γ-氨基丁酸能特征。同样，在非洲爪蟾卵母细胞中进行的体外电生理学研究发现，急性接触甲苯会降低N-甲基-D-天冬氨酸受体信号传导。最后，在一个慢性间歇性接触甲苯（10000 ppm）的青少年啮齿动物模型中，我们发现虽然甲苯接触不影响初始学习，但在工具性条件反射范式中，当反应-结果关系逆转或退化时，它会导致学习更新方面出现缺陷。在获取奖励需要付出更多努力时，也存在组间差异；接触甲苯的动物对累进比率时间表和延迟折扣的敏感性较低。这些行为缺陷伴随着成年期海马体、前额叶皮质和腹内侧纹状体中N-甲基-D-天冬氨酸受体和γ-氨基丁酸受体亚基表达的变化，这些区域在行为灵活性和决策中具有公认的作用。总体而言，我们的数据表明，接触甲苯足以在谷氨酸能和γ-氨基丁酸能系统以及适应性行为中诱导适应性变化，这些变化可能是青少年吸入剂滥用后所观察到的缺陷的基础，包括对进一步药物使用的易感性。
