Division of Analytical Psychopharmacology, Nathan Kline Institute for Psychiatric Research, Orangeburg, New York, United States of America.
PLoS One. 2012;7(5):e36743. doi: 10.1371/journal.pone.0036743. Epub 2012 May 14.
While the etiology of depression is not clearly understood at the present time, this mental disorder is thought be a complex and multifactorial trait with important genetic and environmental contributing factors.
METHODOLOGY/PRINCIPAL FINDINGS: The role of the endocannabinoid (eCB) system in depressive behavior was examined in Wistar Kyoto (WKY) rat strain, a genetic model of depression. Our findings revealed selective abnormalities in the eCB system in the brains of WKY rats compared to Wistar (WIS) rats. Immunoblot analysis indicated significantly higher levels of fatty acid amide hydrolase (FAAH) in frontal cortex and hippocampus of WKY rats with no alteration in the level of N-arachidonyl phosphatidyl ethanolamine specific phospholipase-D (NAPE-PLD). Significantly higher levels of CB1 receptor-mediated G-protein coupling and lower levels of anandamide (AEA) were found in frontal cortex and hippocampus of WKY rats. While the levels of brain derived neurotropic factor (BDNF) were significantly lower in frontal cortex and hippocampus of WKY rats compared to WIS rats, pharmacological inhibition of FAAH elevated BDNF levels in WKY rats. Inhibition of FAAH enzyme also significantly increased sucrose consumption and decreased immobility in the forced swim test in WKY rats.
CONCLUSIONS/SIGNIFICANCE: These findings suggest a critical role for the eCB system and BDNF in the genetic predisposition to depressive-like behavior in WKY rats and point to the potential therapeutic utility of eCB enhancing agents in depressive disorder.
尽管目前人们对抑郁症的病因还没有明确的认识，但这种精神障碍被认为是一种复杂的多因素特征，具有重要的遗传和环境因素。
方法/主要发现：本研究考察了内源性大麻素（eCB）系统在抑郁行为Wistar Kyoto（WKY）大鼠模型中的作用，WKY 大鼠是一种抑郁的遗传模型。我们的研究结果表明，与 Wistar（WIS）大鼠相比，WKY 大鼠大脑中的 eCB 系统存在选择性异常。免疫印迹分析表明，WKY 大鼠前额皮质和海马中的脂肪酸酰胺水解酶（FAAH）水平显著升高，而 N-花生四烯酸磷酰乙醇胺特异性磷脂酶-D（NAPE-PLD）水平没有改变。WKY 大鼠前额皮质和海马中的 CB1 受体介导的 G 蛋白偶联水平显著升高，而大麻素（AEA）水平降低。与 WIS 大鼠相比，WKY 大鼠前额皮质和海马中的脑源性神经营养因子（BDNF）水平显著降低，而 FAAH 的药理学抑制可提高 WKY 大鼠的 BDNF 水平。FAAH 酶的抑制也显著增加了 WKY 大鼠蔗糖的摄入量，并减少了它们在强迫游泳试验中的不动时间。
结论/意义：这些发现表明，eCB 系统和 BDNF 在 WKY 大鼠抑郁样行为的遗传易感性中起着关键作用，并指出了增强内源性大麻素的药物在抑郁症中的潜在治疗用途。
