Department of Biotechnology and Life Sciences, University of Insubria, 21052 Busto Arsizio, VA, Italy.
Neuroscience Center, University of Insubria, 21052 Busto Arsizio, VA, Italy.
Int J Mol Sci. 2017 Oct 4;18(10):2094. doi: 10.3390/ijms18102094.
Adolescence represents a vulnerable period for the psychiatric consequences of delta9-tetrahydrocannabinol (Δ⁸-THC) exposure, however, the molecular underpinnings of this vulnerability remain to be established. Histone modifications are emerging as important epigenetic mechanisms involved in the etiopathogenesis of psychiatric diseases, thus, we investigated the impact of chronic Δ⁸-THC exposure on histone modifications in different brain areas of female rats. We checked histone modifications associated to both transcriptional repression (H3K9 di- and tri-methylation, H3K27 tri-methylation) and activation (H3K9 and H3K14 acetylation) after adolescent and adult chronic Δ⁸-THC exposure in the hippocampus, nucleus accumbens, and amygdala. Chronic exposure to increasing doses of Δ⁸-THC for 11 days affected histone modifications in a region- and age-specific manner. The primary effect in the adolescent brain was represented by changes leading to transcriptional repression, whereas the one observed after adult treatment led to transcriptional activation. Moreover, only in the adolescent brain, the primary effect was followed by a homeostatic response to counterbalance the Δ⁸-THC-induced repressive effect, except in the amygdala. The presence of a more complex response in the adolescent brain may be part of the mechanisms that make the adolescent brain vulnerable to Δ⁸-THC adverse effects.
青春期是受 δ9-四氢大麻酚（Δ⁸-THC）暴露影响出现精神后果的脆弱时期，然而，这种脆弱性的分子基础仍有待确定。组蛋白修饰作为涉及精神疾病发病机制的重要表观遗传机制而出现，因此，我们研究了慢性 Δ⁸-THC 暴露对雌性大鼠不同大脑区域组蛋白修饰的影响。我们检查了与转录抑制（H3K9 二甲基和三甲基化、H3K27 三甲基化）和激活（H3K9 和 H3K14 乙酰化）相关的组蛋白修饰，这些修饰在海马体、伏隔核和杏仁核中分别在青春期和成年期慢性暴露于 Δ⁸-THC 后出现。11 天内慢性接触递增剂量的 Δ⁸-THC 以区域和年龄特异性的方式影响组蛋白修饰。在青春期大脑中，主要影响表现为导致转录抑制的变化，而成年期治疗后观察到的变化则导致转录激活。此外，只有在青春期大脑中，主要影响之后是一种体内平衡反应，以抵消 Δ⁸-THC 诱导的抑制作用，除了在杏仁核中。青春期大脑中存在更复杂的反应可能是使青春期大脑易受 Δ⁸-THC 不良影响的机制的一部分。
