Cannabinoid CB1 receptor-mediated modulation of evoked dopamine release and of adenylyl cyclase activity in the human neocortex

被引:38
作者
Steffens, M
Engler, C
Zentner, J
Feuerstein, TJ
机构
[1] Neurol Univ Klin, Neurozentrum, Sekt Klin Neuropharmakol, D-79106 Freiburg, Germany
[2] Neurochirurg Univ Klin, Neurozentrum, D-79106 Freiburg, Germany
关键词
anandamide; binding assay; cAMP accumulation; cannabinoid CB1 receptor; dopamine release; endocannabinoid; human neocortex;
D O I
10.1038/sj.bjp.0705706
中图分类号
R9 [药学];
学科分类号
1007 ;
摘要
1 The present study investigated the binding characteristics of various ligands to cannabinoid CB1 receptors in human neocortex and amygdala. In addition, the functionality of CB1 receptors in the human neocortex was assessed by examining the effects of CB1 receptor ligands on evoked [H-3]-dopamine ( DA) release in superfused brain slices and on synaptosomal cAMP accumulation. 2 Saturation-binding assays in human neocortical and amygdala synaptosomes using a radiolabelled cannabinoid receptor agonist ([H-3]-CP55.940) revealed pK(d) values of 8.96 and 8.63, respectively. The numbers of binding sites (B-max) were 3.99 and 2.67 pmol ( mg protein)(-1), respectively. 3 Various cannabinoid receptor ligands inhibited [H-3]-CP55.940 binding with rank order potencies corresponding to those of previous studies in animal tissues. 4 Electrically evoked [H-3]-DA release from human neocortical slices was inhibited by CP55.940 ( IC50 6.76 nM, I-max 65%) and strongly enhanced by the cannabinoid receptor antagonist AM251. However, [H-3]-DA release was not influenced in rat neocortex. In human tissue, the estimated endocannabinoid concentration in the biophase of the release-modulating CB1 receptors was 1.07 nM, expressed in CP55.940 units. 5 K+-evoked [H-3]-DA release in the presence of tetrodotoxin (TTX) was strongly inhibited by CP55.940 in humans, but not in rats. 6 In human tissue, CP55.940 inhibited forskolin-stimulated cAMP accumulation (IC50 20.89 nM, I-max 35%). AM251 blocked this effect and per se increased forskolin-stimulated cAMP accumulation by -20%. 7 In conclusion, cannabinoids modulate [(3) H]-DA release and adenylyl cyclase activity in the human neocortex. CB1 receptors are located on dopaminergic nerve terminals and seem to be tonically activated by endocannabinoids.
引用
收藏
页码:1193 / 1203
页数:11
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