Department of Physiology, Anatomy and Genetics, University of Oxford, Oxford, UK [2] Oxford Parkinson's Disease Centre, University of Oxford, Oxford, UK [3] Department of Pharmacology, University of Oxford, Oxford, UK.
Neuropsychopharmacology. 2011 Aug;36(9):1811-22. doi: 10.1038/npp.2011.62. Epub 2011 Apr 20.
Dopamine (DA) neurotransmission in the nucleus accumbens (NAc) is critically involved in normal as well as maladaptive motivated behaviors including drug addiction. Whether the striatal neuromodulator nitric oxide (NO) influences DA release in NAc is unknown. We investigated whether exogenous NO modulates DA transmission in NAc core and how this interaction varies depending on the frequency of presynaptic activation. We detected DA with cyclic voltammetry at carbon-fiber microelectrodes in mouse NAc in slices following stimuli spanning a full range of DA neuron firing frequencies (1-100 Hz). NO donors 3-morpholinosydnonimine hydrochloride (SIN-1) or z-1-[N-(3-ammoniopropyl)-N-(n-propyl)amino]diazen-1-ium-1,2-diolate (PAPA/NONOate) enhanced DA release with increasing stimulus frequency. This NO-mediated enhancement of frequency sensitivity of DA release was not prevented by inhibition of soluble guanylyl cyclase (sGC), DA transporters, or large conductance Ca(2+)-activated K(+) channels, and did not require glutamatergic or GABAergic input. However, experiments to identify whether frequency-dependent NO effects were mediated via changes in powerful acetylcholine-DA interactions revealed multiple components to NO modulation of DA release. In the presence of a nicotinic receptor antagonist (dihydro-β-erythroidine), NO donors increased DA release in a frequency-independent manner. These data suggest that NO in the NAc can modulate DA release through multiple GC-independent neuronal mechanisms whose net outcome varies depending on the activity in DA neurons and accumbal cholinergic interneurons. In the presence of accumbal acetylcholine, NO promotes the sensitivity of DA release to presynaptic activation, but with reduced acetylcholine input, NO will promote DA release in an activity-independent manner through a direct action on dopaminergic terminals.
伏隔核（NAc）中的多巴胺（DA）神经传递对于正常和适应不良的动机行为（包括药物成瘾）至关重要。纹状体神经调质一氧化氮（NO）是否影响 NAc 中的 DA 释放尚不清楚。我们研究了外源性 NO 是否调节 NAc 核心中的 DA 传递，以及这种相互作用如何根据突触前激活的频率而变化。我们在切片中使用碳纤维微电极通过循环伏安法检测 DA，刺激范围涵盖 DA 神经元放电频率的全范围（1-100 Hz）。NO 供体 3-吗啉代-sydnonimine 盐酸盐（SIN-1）或 z-1-[N-（3-氨丙基）-N-（正丙基）氨基]二氮-1-基-1,2-二醇酸盐（PAPA/NONOate）随着刺激频率的增加增强了 DA 的释放。这种 NO 介导的 DA 释放频率敏感性增强不受可溶性鸟苷酸环化酶（sGC）、DA 转运体或大电导钙激活钾（Ca2+）通道的抑制作用的影响，也不需要谷氨酸能或 GABA 能输入。然而，为了确定频率依赖性的 NO 效应是否通过改变强大的乙酰胆碱-DA 相互作用来介导，实验揭示了 NO 调节 DA 释放的多种成分。在烟碱受体拮抗剂（二氢-β-erythroidine）存在的情况下，NO 供体以频率独立的方式增加 DA 释放。这些数据表明，NAc 中的 NO 可以通过多种 GC 独立的神经元机制来调节 DA 释放，其净结果取决于 DA 神经元和伏隔核胆碱能中间神经元的活动。在伏隔核乙酰胆碱存在的情况下，NO 促进 DA 释放对突触前激活的敏感性，但随着乙酰胆碱输入的减少，NO 将以不依赖于活动的方式通过直接作用于多巴胺能末梢来促进 DA 释放。
