Viggiano D, Ruocco L A, Pignatelli M, Grammatikopoulos G, Sadile A G
Human Anatomy, II University of Naples, Italy.
Neurosci Biobehav Rev. 2003 Jan-Mar;27(1-2):129-39. doi: 10.1016/s0149-7634(03)00015-0.
Several evidences suggest that endocannabinoids exert a neurotrophic effect on developing mesencephalic dopamine neurons. Since an altered mesocorticolimbic system seems to underlie hyperactivity and attention deficit in clinical and animal studies of attention deficit hyperactivity disorder (ADHD), prenatal elevation of anandamide has been induced in Naples high excitability (NHE) rats by inhibition of its reuptake. To this aim, pregnant NHE and random-bred females received a subcutaneous injection of AM-404 (1 mg/kg) or vehicle daily from E11 until E20. Young adult male offsprings were exposed to a spatial novelty (Làt-maze) for 30 min and the behavior was videotaped and analysed for indices of activity (travelled distance, rearing frequency) and attention (rearing duration). Moreover, morphological analysis of the brains was carried out that pertained to cytochrome oxydase as marker of metabolic activity and thyrosine hydroxylase as marker of the dopamine systems. The results indicate that prenatal AM-404 treatment significantly reduces activity by about 20% during the entire testing period and modifies the distribution of scanning times towards short duration episodes in the first part of the test only in NHE-treated rats. In addition, image analysis revealed a significant increase in relative optical density of TH+terminals in the dorsal striatum and substantia nigra of AM-404 treated NHE rats and minor changes in the dorsal cortex of AM-404 treated NRB rats. The data suggest a corrected unbalance between the two dopamine systems that apparently leads to reduced hyperactivity and modified scanning times in this animal model of ADHD. This, in turn, might open new strategies in the treatment of a subset of ADHD cases.
多项证据表明，内源性大麻素对发育中的中脑多巴胺神经元具有神经营养作用。由于在注意力缺陷多动障碍（ADHD）的临床和动物研究中，中脑皮质边缘系统的改变似乎是多动和注意力缺陷的基础，因此通过抑制阿南酰胺的再摄取，在那不勒斯高兴奋性（NHE）大鼠中诱导了其产前升高。为此，从胚胎第11天（E11）到第20天（E20），怀孕的NHE大鼠和随机繁殖的雌性大鼠每天皮下注射AM - 404（1毫克/千克）或赋形剂。将年轻成年雄性后代置于空间新奇环境（Lat迷宫）中30分钟，对其行为进行录像，并分析活动指标（行进距离、竖毛频率）和注意力指标（竖毛持续时间）。此外，对大脑进行了形态学分析，以细胞色素氧化酶作为代谢活性的标志物，酪氨酸羟化酶作为多巴胺系统的标志物。结果表明，产前AM - 404治疗在整个测试期间显著降低了约20%的活动量，并且仅在接受NHE治疗的大鼠中，在测试的第一部分将扫描时间的分布改变为短持续时间的发作。此外，图像分析显示，在接受AM - 404治疗的NHE大鼠的背侧纹状体和黑质中，TH + 终末的相对光密度显著增加，而在接受AM - 404治疗的NRB大鼠的背侧皮质中变化较小。数据表明，在这个ADHD动物模型中，两个多巴胺系统之间的不平衡得到了纠正，这显然导致了多动减少和扫描时间改变。这反过来可能为治疗一部分ADHD病例开辟新的策略。
