Yin Henry H, Lovinger David M
Laboratory for Integrative Neuroscience, National Institute on Alcohol Abuse and Alcoholism, National Institutes of Health, Bethesda, MD 20892, USA.
Proc Natl Acad Sci U S A. 2006 May 23;103(21):8251-6. doi: 10.1073/pnas.0510797103. Epub 2006 May 12.
The mechanisms underlying modulation of corticostriatal synaptic transmission by D2-like receptors (D2Rs) have been controversial. A recent study suggested that D2Rs inhibit glutamate release at this synapse, but only during high-frequency synaptic activation. Because the release of postsynaptic endocannabinoids (eCBs), which act as retrograde messengers to inhibit presynaptic glutamate release, can be triggered by D2R activation and intense synaptic activation, such a mechanism could mediate dopaminergic modulation of corticostriatal transmission. Here, we show that D2R activation reduces excitatory transmission onto striatal medium spiny neurons at a stimulation frequency of 20 Hz but not at 1 Hz. This form of inhibition requires CB1 receptor activation, as evidenced by the fact that it is blocked by AM251 [N-(piperidin-1-yl)-1-(2,4-dichlorophenyl)-5-(4-chlorophenyl)-4-methyl-1H-pyrazole-3-carboxamide], a CB1 antagonist, and is absent in CB1 knockout mice. It is also blocked by postsynaptic intracellular calcium chelation, by group I metabotropic glutamate receptor antagonism, and by inhibition of postsynaptic phospholipase C. These results demonstrate a previously unrecognized role for retrograde eCB signaling in reversible and frequency-specific inhibition of glutamate release by the activation of striatal D2Rs.
D2样受体（D2Rs）对皮质纹状体突触传递的调节机制一直存在争议。最近的一项研究表明，D2Rs仅在高频突触激活时抑制该突触处的谷氨酸释放。由于作为逆行信使抑制突触前谷氨酸释放的突触后内源性大麻素（eCBs）的释放可由D2R激活和强烈的突触激活触发，这样一种机制可能介导多巴胺能对皮质纹状体传递的调节。在此，我们表明，D2R激活在20 Hz的刺激频率下可降低对纹状体中等棘状神经元的兴奋性传递，但在1 Hz时则不然。这种抑制形式需要CB1受体激活，这一点可由以下事实证明：它被CB1拮抗剂AM251 [N-（哌啶-1-基）-1-（2,4-二氯苯基）-5-（4-氯苯基）-4-甲基-1H-吡唑-3-甲酰胺]阻断，且在CB1基因敲除小鼠中不存在。它也可被突触后细胞内钙螯合、I组代谢型谷氨酸受体拮抗作用以及突触后磷脂酶C的抑制所阻断。这些结果证明了逆行eCB信号在通过激活纹状体D2Rs对谷氨酸释放进行可逆性和频率特异性抑制方面的一个此前未被认识到的作用。
