Beckley Jacob T, Randall Patrick K, Smith Rachel J, Hughes Benjamin A, Kalivas Peter W, Woodward John J
Department of Neuroscience, Medical University of South Carolina, Charleston, SC, USA.
Center for Drug and Alcohol Programs, Department of Psychiatry, Medical University of South Carolina, Charleston, SC, USA.
Addict Biol. 2016 May;21(3):530-46. doi: 10.1111/adb.12235. Epub 2015 Mar 6.
Abused inhalants are voluntarily inhaled at high concentrations to produce intoxicating effects. Results from animal studies show that the abused inhalant toluene triggers behaviors, such as self-administration and conditioned place preference, which are commonly associated with addictive drugs. However, little is known about how toluene affects neurons within the nucleus accumbens (NAc), a brain region within the basal ganglia that mediates goal-directed behaviors and is implicated in the development and maintenance of addictive behaviors. Here we report that toluene inhibits a component of the after-hyperpolarization potential, and dose-dependently inhibits N-methyl-D-aspartate (NMDA)-mediated currents in rat NAc medium spiny neurons (MSN). Moreover, using the multivariate statistical technique, partial least squares discriminative analysis to analyze electrophysiological measures from rat NAc MSNs, we show that toluene induces a persistent depression of α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA)-mediated currents in one subtype of NAc MSNs, and that the electrophysiological features of MSN neurons predicts their sensitivity to toluene. The CB1 receptor antagonist AM281 blocked the toluene-induced long-term depression of AMPA currents, indicating that this process is dependent on endocannabinoid signaling. The neuronal identity of recorded cells was examined using dual histochemistry and shows that toluene-sensitive NAc neurons are dopamine D2 MSNs that express preproenkephalin mRNA. Overall, the results from these studies indicate that physiological characteristics obtained from NAc MSNs during whole-cell patch-clamp recordings reliably predict neuronal phenotype, and that the abused inhalant toluene differentially depresses excitatory neurotransmission in NAc neuronal subtypes.
滥用吸入剂会被人主动高浓度吸入以产生中毒效果。动物研究结果表明，被滥用的吸入剂甲苯会引发一些行为，比如自我给药和条件性位置偏爱，这些行为通常与成瘾性药物有关。然而，关于甲苯如何影响伏隔核（NAc）内的神经元，人们却知之甚少。伏隔核是基底神经节内的一个脑区，介导目标导向行为，并与成瘾行为的发展和维持有关。在此我们报告，甲苯会抑制超极化后电位的一个成分，并剂量依赖性地抑制大鼠NAc中型多棘神经元（MSN）中N-甲基-D-天冬氨酸（NMDA）介导的电流。此外，我们使用多元统计技术——偏最小二乘判别分析来分析大鼠NAc MSN的电生理指标，结果表明甲苯会导致NAc MSN一种亚型中α-氨基-3-羟基-5-甲基-4-异恶唑丙酸（AMPA）介导的电流持续抑制，并且MSN神经元的电生理特征可预测其对甲苯的敏感性。CB1受体拮抗剂AM281可阻断甲苯诱导的AMPA电流的长期抑制，这表明该过程依赖于内源性大麻素信号传导。使用双重组织化学检查记录细胞的神经元身份，结果表明对甲苯敏感的NAc神经元是表达前脑啡肽原mRNA的多巴胺D2 MSN。总体而言，这些研究结果表明，在全细胞膜片钳记录过程中从NAc MSN获得的生理特征能够可靠地预测神经元表型，并且被滥用的吸入剂甲苯会差异性地抑制NAc神经元亚型中的兴奋性神经传递。
