Venton B Jill, Seipel Andrew T, Phillips Paul E M, Wetsel William C, Gitler Daniel, Greengard Paul, Augustine George J, Wightman R Mark
Department of Chemistry, Neuroscience Center, University of North Carolina, Chapel Hill, North Carolina 27599, USA.
J Neurosci. 2006 Mar 22;26(12):3206-9. doi: 10.1523/JNEUROSCI.4901-04.2006.
Cocaine primarily exerts its behavioral effects by enhancing dopaminergic neurotransmission, amplifying dopamine-encoded sensorimotor integration. The presumed mechanism for this effect is inhibition of the dopamine transporter, which blocks dopamine uptake and prolongs the duration of dopamine in the extracellular space. However, there is growing evidence that cocaine can also augment dopamine release. Here, we directly monitored the actions of cocaine on dopamine release by using electrochemical detection to measure extracellular dopamine in the striatum of anesthetized mice. Cocaine enhanced the levels of striatal dopamine produced by electrical stimulation of dopaminergic neurons. Even after pretreatment with alpha-methyl-p-tyrosine, which depletes the readily releasable pool of dopamine, cocaine was still capable of elevating dopamine levels. This suggests that cocaine enhances dopamine release by mobilizing a reserve pool of dopamine-containing synaptic vesicles. To test this hypothesis, we examined electrically evoked dopamine release in synapsin I/II/III triple knock-out mice, which have impaired synaptic vesicle reserve pools. Knock-out of synapsins greatly reduced the ability of cocaine to enhance dopamine release with long stimulus trains or after depletion of the newly synthesized pool. We therefore conclude that cocaine enhances dopamine release and does so by mobilizing a synapsin-dependent reserve pool of dopamine-containing synaptic vesicles. This capacity to enhance exocytotic release of dopamine may be important for the psychostimulant actions of cocaine.
可卡因主要通过增强多巴胺能神经传递来发挥其行为效应，放大由多巴胺编码的感觉运动整合。这种效应的推测机制是抑制多巴胺转运体，该转运体可阻止多巴胺摄取并延长细胞外空间中多巴胺的持续时间。然而，越来越多的证据表明，可卡因也可以增加多巴胺释放。在此，我们通过电化学检测来测量麻醉小鼠纹状体中的细胞外多巴胺，直接监测可卡因对多巴胺释放的作用。可卡因增强了电刺激多巴胺能神经元所产生的纹状体多巴胺水平。即使在用α-甲基-p-酪氨酸预处理耗尽了易于释放的多巴胺池之后，可卡因仍能够提高多巴胺水平。这表明可卡因通过动员含多巴胺的突触小泡储备池来增加多巴胺释放。为了验证这一假设，我们检测了突触素I/II/III三敲除小鼠的电诱发多巴胺释放，这些小鼠的突触小泡储备池受损。敲除突触素极大地降低了可卡因在长刺激序列或新合成池耗尽后增强多巴胺释放的能力。因此，我们得出结论，可卡因通过动员依赖突触素的含多巴胺突触小泡储备池来增加多巴胺释放。这种增强多巴胺胞吐释放的能力可能对可卡因的精神兴奋作用很重要。
