Malloul Hanaa, Bennis Mohammed, Bonzano Sara, Gambarotta Giovanna, Perroteau Isabelle, De Marchis Silvia, Ba-M'hamed Saadia
Laboratory of Pharmacology, Neurobiology and Behavior (URAC-37), Faculty of Sciences Semlalia, Cadi Ayyad University, Marrakech, Morocco.
Department of Life Sciences and Systems Biology, University of Turin, Turin, Italy.
Front Neurosci. 2018 Feb 6;12:35. doi: 10.3389/fnins.2018.00035. eCollection 2018.
Thinners are highly toxic chemicals widely employed as organic solvents in industrial and domestic use. They have psychoactive properties when inhaled, and their chronic abuse as inhalants is associated with severe long-term health effects, including brain damage and cognitive-behavioral alterations. Yet, the sites and mechanisms of action of these compounds on the brain are far from being fully understood. Here, we investigated the consequences of paint thinner inhalation in adult male mice. Depression-like behaviors and an anxiolytic effect were found following repeated exposure in chronic treatments lasting 12 weeks. Both subchronic (6 weeks) and chronic treatments impaired learning and memory functions, while no changes were observed after acute treatment. To investigate possible molecular/structural alterations underlying such behavioral changes, we focused on the hippocampus. Notably, prolonged, but not acute thinner inhalation strongly affected adult neurogenesis in the dentate gyrus (DG), reducing progenitor cell proliferation after chronic treatments and impairing the survival of newborn neurons following both chronic and subchronic treatments. Furthermore, a down-regulation in the expression of BDNF and NMDA receptor subunits as well as a reduction in CREB expression/phosphorylation were found in the hippocampi of chronically treated mice. Our findings demonstrate for the first time significant structural and molecular changes in the adult hippocampus after prolonged paint thinner inhalation, indicating reduced hippocampal neuroplasticity and strongly supporting its implication in the behavioral dysfunctions associated to inhalant abuse.
稀释剂是剧毒化学品，在工业和家庭用途中广泛用作有机溶剂。吸入时它们具有精神活性，长期滥用吸入这些物质会导致严重的长期健康影响，包括脑损伤和认知行为改变。然而，这些化合物对大脑的作用部位和机制远未被完全了解。在此，我们研究了成年雄性小鼠吸入油漆稀释剂的后果。在持续12周的慢性治疗中反复接触后，发现出现了类似抑郁的行为和抗焦虑作用。亚慢性（6周）和慢性治疗均损害了学习和记忆功能，而急性治疗后未观察到变化。为了研究这些行为变化背后可能的分子/结构改变，我们聚焦于海马体。值得注意的是，长期而非急性吸入稀释剂强烈影响齿状回（DG）中的成年神经发生，慢性治疗后减少祖细胞增殖，慢性和亚慢性治疗后均损害新生神经元的存活。此外，在慢性治疗小鼠的海马体中发现脑源性神经营养因子（BDNF）和N-甲基-D-天冬氨酸（NMDA）受体亚基的表达下调，以及环磷腺苷效应元件结合蛋白（CREB）表达/磷酸化减少。我们的研究结果首次证明，长期吸入油漆稀释剂后成年海马体出现了显著的结构和分子变化，表明海马体神经可塑性降低，并有力地支持了其与吸入性药物滥用相关的行为功能障碍有关。
