CB1 receptor antagonism increases hippocampal acetylcholine release:: Site and mechanism of action
CB1 receptor antagonism increases hippocampal acetylcholine release:: Site and mechanism of action
复制标题
DOI：
10.1124/mol.106.024661
复制
发表时间：
2006-10-01
影响因子：
3.6
通讯作者：
Nomikos, George G.
中科院分区：
文献类型：
--
作者：
Degroot, Aldemar;Kofalvi, Attila;Nomikos, George G.
有证据表明，大麻素受体的阻断增加了大脑皮层区域中乙酰胆碱（ACh）的释放。虽然它被认为是通过CB 1受体（CB 1 R）拮抗作用介导的这种类型的效果，最近在体外功能研究表明非CB 1 R参与。此外，精确的神经解剖部位和这种效应的确切机制都不清楚。我们彻底研究了这些问题，使用CB 1 R拮抗剂的全身和局部给药的组合，不同的方法在体内微透析，CB 1 R敲除（KO）小鼠，乙酰胆碱的组织测量，和免疫化学。首先，我们发现全身注射CB 1 R拮抗剂N-（哌啶-1-基）-5-（4-氯苯基）-1-（2，4-二氯苯基）-4-甲基-1H-吡唑-3-甲酰胺盐酸盐（SR 141716 A）和N-（哌啶-1-基）-5-（4-碘苯基）-1-（2，4-二氯苯基）4-甲基-1H-吡唑-3-甲酰胺（AM 251）剂量依赖性地增加海马ACh流出。同样，局部海马，但不是隔，SR 141716 A或AM 251的输注增加海马ACh释放。值得注意的是，全身给予CB 1 R拮抗剂对海马ACh释放的刺激作用在CB 1 R KO小鼠中完全消失。与野生型对照组相比，CB 1 R KO小鼠具有相似的基础但更高的应激增强海马ACh水平。有趣的是，多巴胺D-1受体拮抗剂抵消了CB 1 R阻断对海马ACh水平的刺激作用。最后，免疫组织化学方法显示，CB 1受体阳性神经末梢的比例很高，发现在海马和确认的共定位的CB 1受体与胆碱能和多巴胺能神经末梢。总之，海马ACh释放可能通过位于胆碱能和多巴胺能神经元投射上的CB（1）受体特异性控制，CB 1 R拮抗作用增加海马ACh释放，可能通过直接解除ACh释放抑制和间接增加D-1受体上的多巴胺能神经传递。
Evidence indicates that blockade of cannabinoid receptors increases acetylcholine (ACh) release in brain cortical regions. Although it is assumed that this type of effect is mediated through CB1 receptor (CB1R) antagonism, several in vitro functional studies recently have suggested non-CB1R involvement. In addition, neither the precise neuroanatomical site nor the exact mechanisms underlying this effect are known. We thoroughly examined these issues using a combination of systemic and local administration of CB1R antagonists, different methods of in vivo microdialysis, CB1R knockout (KO) mice, tissue measurements of ACh, and immunochemistry. First, we showed that systemic injections of the CB1R antagonists N-(piperidin-1-yl)-5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4-methyl-1H-pyrazole-3-carboximide hydrochloride (SR141716A) and N-(piperidin-1-yl)-5-(4-iodophenyl)-1-(2, 4-dichlorophenyl)4-methyl-1H-pyrazole-3-carboxamide (AM251) dose-dependently increased hippocampal ACh efflux. Likewise, local hippocampal, but not septal, infusions of SR141716A or AM251 increased hippocampal ACh release. It is noteworthy that the stimulatory effects of systemically administered CB1R antagonists on hippocampal ACh release were completely abolished in CB1R KO mice. CB1R KO mice had similar basal but higher stress-enhanced hippocampal ACh levels compared with wild-type controls. It is interesting that dopamine D-1 receptor antagonism counteracted the stimulatory effect of CB1R blockade on hippocampal ACh levels. Finally, immunohistochemical methods revealed that a high proportion of CB1R-positive nerve terminals were found in hippocampus and confirmed the colocalization of CB1 receptors with cholinergic and dopaminergic nerve terminals. In conclusion, hippocampal ACh release may specifically be controlled through CB(1)Rs located on both cholinergic and dopaminergic neuronal projections, and CB1R antagonism increases hippocampal ACh release, probably through both a direct disinhibition of ACh release and an indirect increase in dopaminergic neurotransmission at the D-1 receptors.