Cubeddu L X, Hoffmann I S, Talmaciu R K
Division of Pharmacology, Pharmacy Faculty, Central University of Venezuela, Caracas.
Ann N Y Acad Sci. 1990;604:452-61. doi: 10.1111/j.1749-6632.1990.tb32011.x.
Results obtained from our in vitro studies employing superfused slices obtained from three functionally different brain regions rich in DA axon terminals were discussed. Striking qualitative and quantitative similarities were found for the modulation of DA release from the nucleus caudate and the OT of the rabbit. However, the PFC DA terminals showed important differences from the nigrostriatal and mesolimbic DA terminals. Although release modulatory D2 DA autoreceptors could also be demonstrated in superfused slices of the PFC, our results suggest that the cortical nerve terminals may have a lower number of functional autoreceptors or a reduced efficiency of coupling between receptors and inhibition of release. Either possibility could explain (a) the poor inhibitory efficacy of the agonists, (b) the small facilitatory effect of the antagonists, (c) the disproportionate increase in transmitter overflow produced by neuronal uptake inhibitors, and (d) the lack of synergism between uptake inhibitors and DA antagonists. When the efficacy of the autoreceptor mechanisms was evaluated at stimulation frequencies comparable to the in vivo firing rates reported for each of the three neuronal groups, it was found that DA release from the striatum and the OT was tightly modulated by presynaptic D2 DA receptors; whereas release from PFC was not. We propose that the autoreceptor-mediated control of DA release from PFC may not function in vivo, even though modulation of release by presynaptic D2 DA receptors from PFC terminals could be demonstrated under specific experimental conditions in vitro. However, it is envisaged that if in vivo firing rate of the PFC DA neurons is reduced, the inhibitory actions of DA agonists on DA release may be regained. From these and other studies it is apparent that drug effects on autoreceptors are highly dependent on the rate and duration of stimulation applied to a specific neuronal group. We propose that the basal status of activity of a specific neuronal target could determine the type and magnitude of the effect produced by a therapeutic agent acting at release modulatory receptors. The neuronal activity (firing rate and pattern) may be affected by physiological status, disease, and by current or previous drug treatments. The mechanisms by which PFC DA terminals release a larger proportion of their storage pool compared to other mesotelencephalic DA terminals is unknown and may represent a compensatory mechanism to the continuous rapid firing rates at which these neurons are exposed in vivo.(ABSTRACT TRUNCATED AT 400 WORDS)
讨论了我们利用从富含多巴胺（DA）轴突终末的三个功能不同的脑区获取的灌流脑片进行体外研究所得的结果。在兔尾状核和视束中，多巴胺释放的调节在定性和定量方面都存在显著相似性。然而，前额叶皮质（PFC）的多巴胺终末与黑质纹状体及中脑边缘多巴胺终末存在重要差异。尽管在PFC灌流脑片中也能证实存在释放调节性D2多巴胺自身受体，但我们的结果表明，皮质神经终末可能具有较少数量的功能性自身受体，或者受体与释放抑制之间的偶联效率降低。这两种可能性都可以解释：（a）激动剂的抑制效力较差；（b）拮抗剂的促进作用较小；（c）神经元摄取抑制剂导致递质溢出不成比例地增加；（d）摄取抑制剂与多巴胺拮抗剂之间缺乏协同作用。当在与报道的三个神经元组各自的体内放电频率相当的刺激频率下评估自身受体机制的效力时，发现纹状体和视束中的多巴胺释放受到突触前D2多巴胺受体的严格调节；而PFC的释放则不受调节。我们提出，尽管在特定体外实验条件下可以证实PFC终末的突触前D2多巴胺受体对释放的调节作用，但PFC多巴胺释放的自身受体介导控制在体内可能不起作用。然而，可以设想，如果PFC多巴胺神经元的体内放电频率降低，多巴胺激动剂对多巴胺释放的抑制作用可能会恢复。从这些研究和其他研究中可以明显看出，药物对自身受体的作用高度依赖于施加于特定神经元组的刺激速率和持续时间。我们提出，特定神经元靶点的基础活动状态可以决定作用于释放调节受体的治疗药物所产生的效应类型和程度。神经元活动（放电频率和模式）可能受到生理状态、疾病以及当前或先前药物治疗的影响。与其他中脑-边缘多巴胺终末相比，PFC多巴胺终末释放其储存池更大比例的机制尚不清楚，可能代表了一种针对这些神经元在体内所暴露的持续快速放电频率的补偿机制。（摘要截选至400字）
