Effect of delta-9-tetrahydrocannabinol on behavioral despair and on pre- and postsynaptic serotonergic transmission
Effect of delta-9-tetrahydrocannabinol on behavioral despair and on pre- and postsynaptic serotonergic transmission
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DOI：
10.1016/j.pnpbp.2012.02.006
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发表时间：
2012-07-02
影响因子：
5.6
通讯作者：
Gobbi, Gabriella
中科院分区：
文献类型：
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作者：
Bambico, Francis Rodriguez;Hattan, Patrick R.;Gobbi, Gabriella
临床前和临床研究表明，直接和间接的大麻素激动剂，包括内源性大麻素的增强剂，通过中枢CB1受体(CB(1)Rs)产生缓解压力、缓解焦虑和抗抑郁的作用。大麻中的主要药理活性成分(-)-反-三角洲(9)-四氢大麻酚(Delta-9-THC)对抑郁行为和5-羟色胺(5-HT)系统的影响尚未广泛阐明，这与抗抑郁药的作用机制有关。在这里，我们显示重复(5天)，但不是单一的(急性)腹腔注射Delta-9-THC(1 mg/kg)在大鼠强迫游泳试验(FST)中发挥抗抑郁药样特性。这种作用是CB1R依赖的，因为它被CB1R拮抗剂利莫那班(1 mg/kg，ip)所阻断。利用体内电生理学，我们证明了Delta-9-THC通过CB1R依赖机制调节中缝背核(DR)5-羟色胺(5-HT)神经元活动。急性静脉注射Delta-9-THC(0.1-1.5 mg/kg)可引起复杂的反应，引起5-羟色胺神经元的兴奋性、抑制性和惰性反应。利莫那班仅阻断兴奋性反应。最后，重复但不是单次注射Delta-9-THC(1 mg/kg，ip)增强了海马区紧张性5-HT1a受体的活性，这是标准抗抑郁药通常引发的突触后事件。这些结果表明，Delta-9-THC和其他CB1R激动剂和内源性大麻素增强剂一样，在低剂量下可能具有抗抑郁特性，并可以作为选择性5-羟色胺再摄取抑制剂等标准抗抑郁剂调节DR和海马区的5-羟色胺传递。(C)2012 Elsevier Inc.保留所有权利。
Preclinical and clinical studies suggest that direct and indirect cannabinoid agonists, including enhancers of endocannabinoids, engender stress-relieving, anxiolytic and antidepressant effects, mediated by central CB1 receptors (CB(1)Rs). The effect of the main pharmacologically active principle in cannabis, (-)-trans-Delta(9)-tetrahydrocannabinol (delta-9-THC), on depressive behavior and on the serotonin (5-HT) system, which is implicated in the mechanism of action of antidepressants, has not been extensively clarified. Here, we showed that repeated (5 days), but not single (acute) intraperitoneal (ip) treatment with delta-9-THC (1 mg/kg) exerts antidepressant-like properties in the rat forced swim test (FST). This effect was CB1R-dependent because it was blocked by the CB1R antagonist rimonabant (1 mg/kg, ip). Using in vivo electrophysiology, we demonstrated that delta-9-THC modulated dorsal raphe (DR) 5-HT neuronal activity through a CB1R-dependent mechanism. Acute intravenous delta-9-THC administration (0.1-1.5 mg/kg) elicited a complex response profile, producing excitatory, inhibitory and inert responses of 5-HT neurons. Only excitatory responses were blocked by rimonabant. Finally, repeated but not single delta-9-THC administration (1 mg/kg, ip) enhanced tonic 5-HT1A receptor activity in the hippocampus, a postsynaptic event commonly elicited by standard antidepressants. These results suggest that delta-9-THC, like other CB1R agonists and endocannabinoid enhancers, may possess antidepressant properties at low doses, and could modulate 5-HT transmission in the DR and hippocampus as standard antidepressants such as selective serotonin reuptake inhibitors. (C) 2012 Elsevier Inc. All rights reserved.