Bambico Francis Rodriguez, Duranti Andrea, Tontini Andrea, Tarzia Giorgio, Gobbi Gabriella
Neurobiological Psychiatry Unit, Department of Psychiatry, McGill University, Montréal, Québec, Canada.
Curr Pharm Des. 2009;15(14):1623-46. doi: 10.2174/138161209788168029.
Among all mental disorders, major depression has the highest rate of prevalence and incidence of morbidity. Currently available antidepressant therapies have limited efficacies; consequently, research on new drugs for the treatment of mood disorders has become increasingly critical. Recent preclinical evidences that cannabinoid agonists and endocannabinoid enhancers, such as the fatty acid amide hydrolase (FAAH) inhibitors, can impact mood regulation have opened a new line of research in antidepressant drug discovery. However, the neurobiological mechanisms linking the endocannabinoid system with the pathophysiology of mood disorders and antidepressant action remain unclarified. In this review, we have presented an update on preclinical data indicating the antidepressant potential of cannabinoid agonists and endocannabinoid enhancers in comparison to standard antidepressants. Data obtained from CB(1) knockout (CB(1)-/-) and FAAH knockout (FAAH-/-) mice have also been examined within this context. We have illustrated how the various classes of antidepressants exert their therapeutic action. In particular, all antidepressants increase the neurotransmission of serotonin after long-term treatment, enhance the tonic activity of hippocampal 5-HT(1A) receptors, promote neurogenesis, and modulate (decrease or increase) the firing activity of noradrenergic neurons. Interestingly, cannabinoid agonists and endocannabinoid enhancers increase serotonin and noradrenergic neuronal firing activity, increase serotonin release in the hippocampus, as well as promote neurogenesis. Since cannabinoid-derived drugs potentiate monoaminergic neurotransmission and hippocampal neurogenesis through distinct pathways compared to classical antidepressants, they may represent an alternative drug class in the pharmacotherapy of mood and other neuropsychiatric disorders.
在所有精神障碍中，重度抑郁症的患病率和发病率最高。目前可用的抗抑郁疗法疗效有限；因此，研发治疗情绪障碍的新药变得愈发关键。近期的临床前证据表明，大麻素激动剂和内源性大麻素增强剂，如脂肪酸酰胺水解酶（FAAH）抑制剂，可影响情绪调节，这为抗抑郁药物的研发开辟了新的研究方向。然而，将内源性大麻素系统与情绪障碍的病理生理学及抗抑郁作用联系起来的神经生物学机制仍未明确。在本综述中，我们介绍了临床前数据的最新情况，这些数据表明与标准抗抑郁药相比，大麻素激动剂和内源性大麻素增强剂具有抗抑郁潜力。在此背景下，我们还研究了从CB(1)基因敲除（CB(1)-/-）和FAAH基因敲除（FAAH-/-）小鼠获得的数据。我们阐述了各类抗抑郁药如何发挥其治疗作用。特别是，所有抗抑郁药在长期治疗后都会增加血清素的神经传递，增强海马体5-HT(1A)受体的紧张性活动，促进神经发生，并调节（降低或增加）去甲肾上腺素能神经元的放电活动。有趣的是，大麻素激动剂和内源性大麻素增强剂会增加血清素和去甲肾上腺素能神经元的放电活动，增加海马体中血清素的释放，同时促进神经发生。由于大麻素衍生药物与经典抗抑郁药相比，通过不同途径增强单胺能神经传递和海马体神经发生，它们可能代表了治疗情绪及其他神经精神障碍药物治疗中的另一类替代药物。
