Center for Neuroscience, Swammerdam Institute for Life Sciences, University of Amsterdam, 1098 XH Amsterdam The Netherlands.
Synapse. 2011 Aug;65(8):814-26. doi: 10.1002/syn.20908. Epub 2011 Mar 21.
This in vitro study investigates and compares the effects of NK3 receptor ligands on the firing rate of rat and guinea pig midbrain dopamine neurons. The findings are discussed in the light of choosing suitable animal models for investigating pharmacological properties of NK3 receptor antagonists, which have been proposed to possess therapeutic activity in neuropsychiatric diseases like e.g. schizophrenia. In vitro midbrain slice preparations of both species were used to record (extracellularly) the firing rates of dopamine neurons located in the substantia nigra (SN) and ventral tegmental area (VTA). Furthermore, the effect of the D2 receptor agonist quinpirole on guinea pig SN and VTA dopamine neurons was investigated. The efficacy of quinpirole in inhibiting guinea pig dopamine neuron firing activity was much less as compared to that of rat dopamine neurons, suggesting a lower dopamine D2 autoreceptor density on the guinea pig neurons. The NK3 receptor agonist senktide induced in subpopulations of rat SN (55%) and VTA (79%) and guinea pig SN (50%) and VTA (21%) dopamine neurons an increase in firing rate. In responsive neurons this effect was concentration-dependent with EC₅₀ values of 3-5 nM (for both species). The selective NK3 receptor antagonist osanetant (100 nM) was able to partly block the senktide-induced increase in firing rates of dopamine neurons and shifted the concentration-response relation curves for senktide to the right (pA₂ values were ~7.5). The fractional block of the senktide responses by osanetant appeared to be larger in guinea pig dopamine neurons, indicating that osanetant is a more potent blocker of NK3 receptor-mediated responses with noncompetitive properties in the guinea pig.
这项体外研究调查并比较了 NK3 受体配体对大鼠和豚鼠中脑多巴胺神经元放电率的影响。研究结果结合选择合适的动物模型来研究 NK3 受体拮抗剂的药理学特性进行了讨论，这些拮抗剂被认为在精神神经疾病（如精神分裂症）中具有治疗活性。本研究使用两种物种的体外中脑切片制备物来记录（细胞外）位于黑质（SN）和腹侧被盖区（VTA）的多巴胺神经元的放电率。此外，还研究了 D2 受体激动剂喹吡罗尔对豚鼠 SN 和 VTA 多巴胺神经元的作用。喹吡罗尔抑制豚鼠多巴胺神经元放电活性的效力明显低于大鼠多巴胺神经元，表明豚鼠神经元上的多巴胺 D2 自身受体密度较低。NK3 受体激动剂 senktide 可使大鼠 SN（55%）和 VTA（79%）以及豚鼠 SN（50%）和 VTA（21%）多巴胺神经元亚群的放电率增加。在反应性神经元中，这种效应呈浓度依赖性，EC₅₀ 值为 3-5 nM（两种物种）。选择性 NK3 受体拮抗剂 osanetant（100 nM）能够部分阻断 senktide 诱导的多巴胺神经元放电率增加，并使 senktide 的浓度-反应关系曲线向右移位（pA₂ 值约为 7.5）。osanetant 对 senktide 反应的分数阻断似乎在豚鼠多巴胺神经元中更大，表明 osanetant 是一种更有效的 NK3 受体介导反应的阻滞剂，在豚鼠中具有非竞争性特性。
