Cobb W S, Abercrombie E D
Center for Molecular and Behavioral Neuroscience, Rutgers University, 197 University Avenue, Newark, NJ, 07102, USA.
Neuroscience. 2003;119(3):777-86. doi: 10.1016/s0306-4522(03)00071-x.
Previously, we have shown that GABA(A) receptors and glutamate receptors in substantia nigra play distinct roles in the regulation of somatodendritic dopamine release. GABAergic input to substantia nigra was found to be the primary determinant of the level of spontaneous somatodendritic dopamine release. In contrast, acute blockade of dopamine receptors by systemic haloperidol administration produced an increase in somatodendritic dopamine release in substantia nigra that was found to be dependent exclusively upon activation of nigral glutamate receptors. The focus of the present study was to identify anatomical structures that may participate in the differential regulation of somatodendritic dopamine release by GABA and glutamate under these two conditions. To this end, we pharmacologically inhibited the activity of either globus pallidus or subthalamic nucleus using microinfusion of the GABA(A) receptor agonist muscimol. The effects of these manipulations on spontaneous efflux of somatodendritic dopamine and on increases in this measure produced by systemic haloperidol administration were determined in ipsilateral substantia nigra using in vivo microdialysis. As observed previously, administration of haloperidol (0.5 mg/kg, i.p.) significantly increased extracellular dopamine in substantia nigra. Microinfusion of muscimol (400 ng/200 nl) into globus pallidus also produced a significant increase in somatodendritic dopamine efflux. When haloperidol was administered systemically in conjunction with microinfusion of muscimol into globus pallidus, an increase in nigral dopamine efflux was observed that was significantly greater than that which was produced singly by muscimol microinfusion into globus pallidus or by systemic haloperidol administration. The additive nature of the increases in somatodendritic dopamine release produced by these two manipulations indicates that independent neural circuitries may be involved. Inactivation of subthalamic nucleus by microinfusion of muscimol (200 ng/100 nl) had no effect on spontaneous somatodendritic dopamine efflux. Muscimol application into subthalamic nucleus, however, completely abolished the stimulatory effect of systemic haloperidol on dendritic dopamine efflux in substantia nigra. The present data extend our previous findings by demonstrating: 1) an important involvement of globus pallidus efferents in the GABAergic regulation of somatodendritic dopamine efflux in substantia nigra under normal conditions and, 2) an emergent predominant role of subthalamic nucleus efferents in the glutamate-dependent increase in somatodendritic dopamine efflux observed after systemic haloperidol administration. Thus, the relative influence of globus pallidus and subthalamic nucleus in the determination of the level of somatodendritic dopamine release in substantia nigra qualitatively varies as a function of dopamine receptor blockade. These findings are relevant to current models of basal ganglia function under both normal and pathological conditions, e.g. Parkinson's disease.
此前，我们已经表明，黑质中的GABA(A)受体和谷氨酸受体在调节树突状多巴胺释放方面发挥着不同作用。研究发现，黑质的GABA能输入是树突状多巴胺自发释放水平的主要决定因素。相比之下，通过全身给予氟哌啶醇急性阻断多巴胺受体，会使黑质中树突状多巴胺释放增加，且发现这完全依赖于黑质谷氨酸受体的激活。本研究的重点是确定在这两种情况下，可能参与GABA和谷氨酸对树突状多巴胺释放进行差异调节的解剖结构。为此，我们通过微量注射GABA(A)受体激动剂蝇蕈醇，从药理学上抑制苍白球或丘脑底核的活性。使用体内微透析技术，在同侧黑质中测定了这些操作对树突状多巴胺自发流出的影响，以及全身给予氟哌啶醇所导致的该指标增加的影响。如先前观察到的，给予氟哌啶醇（0.5mg/kg，腹腔注射）可显著增加黑质细胞外多巴胺水平。向苍白球微量注射蝇蕈醇（400ng/200nl）也会使树突状多巴胺流出显著增加。当全身给予氟哌啶醇并同时向苍白球微量注射蝇蕈醇时，观察到黑质多巴胺流出增加，且显著大于单独向苍白球微量注射蝇蕈醇或全身给予氟哌啶醇所产生的增加量。这两种操作所导致的树突状多巴胺释放增加具有相加性，表明可能涉及独立的神经回路。向丘脑底核微量注射蝇蕈醇（200ng/100nl）使其失活，对树突状多巴胺自发流出没有影响。然而，将蝇蕈醇注入丘脑底核完全消除了全身给予氟哌啶醇对黑质树突状多巴胺流出的刺激作用。目前的数据扩展了我们之前的发现，表明：1）在正常情况下，苍白球传出纤维在黑质树突状多巴胺流出的GABA能调节中起重要作用；2）在全身给予氟哌啶醇后观察到的树突状多巴胺流出依赖谷氨酸增加过程中，丘脑底核传出纤维发挥着新出现的主要作用。因此，苍白球和丘脑底核对黑质树突状多巴胺释放水平的相对影响，在性质上会因多巴胺受体阻断而发生变化。这些发现与正常和病理条件下（如帕金森病）基底神经节功能的当前模型相关。
