Instituto de Neurociencias, Campus de San Juan, Universidad Miguel Hernández-CSIC, San Juan de Alicante, Alicante, Spain.
Br J Pharmacol. 2010 Aug;160(7):1773-84. doi: 10.1111/j.1476-5381.2010.00819.x.
The present study evaluated the role of CB(2) receptors in the regulation of depressive-like behaviours. Transgenic mice overexpressing the CB(2) receptor (CB2xP) were challenged with different types of acute and chronic experimental paradigms to evaluate their response in terms of depressive-like behaviours.
Tail suspension test (TST), novelty-suppressed feeding test (NSFT) and unpredictable chronic mild stress tests (CMS) were carried out in CB2xP mice. Furthermore, acute and chronic antidepressant-like effects of the CB(2) receptor-antagonist AM630 were evaluated by means of the forced swimming test (FST) and CMS, respectively, in wild-type (WT) and CB2xP mice. CB(2) gene expression, brain-derived neurotrophic factor (BDNF) gene and protein expressions were studied in mice exposed to CMS by real-time PCR and immunohistochemistry, respectively.
Overexpression of CB(2) receptors resulted in decreased depressive-like behaviours in the TST and NSFT. CMS failed to alter the TST and sucrose consumption in CB2xP mice. In addition, no changes in BDNF gene and protein expression were observed in stressed CB2xP mice. Interestingly, acute administration of AM630 (1 and 3 mg x kg(-1), i.p.) exerted antidepressant-like effects on the FST in WT, but not in CB2xP mice. Chronic administration of AM630 for 4 weeks (1 mg x kg(-1); twice daily, i.p.) blocked the effects of CMS on TST, sucrose intake, CB(2) receptor gene, BDNF gene and protein expression in WT mice.
Taken together, these results suggest that increased CB(2) receptor expression significantly reduced depressive-related behaviours and that the CB(2) receptor could be a new potential therapeutic target for depressive-related disorders.
本研究评估了 CB(2) 受体在调节抑郁样行为中的作用。过表达 CB(2) 受体（CB2xP）的转基因小鼠接受了不同类型的急性和慢性实验范式的挑战，以评估它们在抑郁样行为方面的反应。
进行了悬尾试验（TST）、新异环境抑制摄食试验（NSFT）和不可预测性慢性轻度应激试验（CMS），以评估 CB2xP 小鼠的行为。此外，通过强迫游泳试验（FST）和 CMS，分别评估了 CB(2) 受体拮抗剂 AM630 的急性和慢性抗抑郁样作用，在野生型（WT）和 CB2xP 小鼠中。通过实时 PCR 和免疫组织化学分别研究了 CMS 暴露后小鼠的 CB(2) 基因表达、脑源性神经营养因子（BDNF）基因和蛋白表达。
CB(2) 受体的过表达导致 TST 和 NSFT 中抑郁样行为减少。CMS 未能改变 CB2xP 小鼠的 TST 和蔗糖消耗。此外，应激 CB2xP 小鼠的 BDNF 基因和蛋白表达没有变化。有趣的是，急性给予 AM630（1 和 3 mg·kg(-1)，i.p.）在 WT 小鼠中表现出抗 FST 的抗抑郁样作用，但在 CB2xP 小鼠中没有。慢性给予 AM630 4 周（1 mg·kg(-1)；每日 2 次，i.p.）阻断了 AM630 对 WT 小鼠 TST、蔗糖摄入、CB(2) 受体基因、BDNF 基因和蛋白表达的 CMS 作用。
综上所述，这些结果表明，增加 CB(2) 受体表达显著减少了与抑郁相关的行为，CB(2) 受体可能成为与抑郁相关疾病的新的潜在治疗靶点。
