Institute of Biochemistry, Biological Research Centre, Temesvári krt. 62., H-6726 Szeged, Hungary; Doctoral School of Theoretical Medicine, Faculty of Medicine, University of Szeged, Dóm tér 10., H-6720 Szeged, Hungary.
Department of Pharmacodynamics and Biopharmacy, Faculty of Pharmacy, University of Szeged, Eötvös u. 6., H-6720 Szeged, Hungary.
Brain Res. 2020 Dec 1;1748:147074. doi: 10.1016/j.brainres.2020.147074. Epub 2020 Aug 26.
In previous studies we have shown that a three-hit animal model of schizophrenia (Wisket rat) has several behavioral impairments related to the disorder along with altered mu-opioid (MOP) and cannabinoid (CB1) receptor signaling. As the dopamine hypothesis of schizophrenia is central to research in the field, the goal of the present study was to investigate dopaminergic D receptor (DR) functions (binding capacity, G-protein activation and expression) in several brain regions (hippocampus, prefrontal cortex, striatum, olfactory bulb, cerebellum, brainstem, cortex and diencephalon) of control (Wistar) and Wisket rats. It was found that the DR mediated maximal activation of G-proteins was substantially higher in hippocampus, striatum and olfactory bulb membranes prepared from the Wisket than in control animals, which was accompanied with lower potency of the DR-mediated G-protein activation. In contrast, enhanced potency was detected in the prefrontal cortex without changes in the maximal activation. In saturation binding assays the maximal binding capacity of DRs was higher in the model animals in cerebral cortex, striatum and lower in the brainstem, while no changes in the dissociation constant values were detected. The DR mRNA expression showed a trend for greater level in the investigated areas, while the DR protein expression was significantly higher of Wisket rats compared to Wistar animals in the hippocampus and in the prefrontal cortex but not in the cerebellum. This study proved that the Wisket animals show altered D receptor expression and function which might be related to the schizophrenia-like symptoms.
在之前的研究中，我们已经表明，精神分裂症的三击动物模型（Wisket 大鼠）具有几种与该疾病相关的行为障碍，以及改变的μ-阿片（MOP）和大麻素（CB1）受体信号。由于精神分裂症的多巴胺假说在该领域的研究中至关重要，本研究的目的是研究几种脑区（海马体、前额叶皮层、纹状体、嗅球、小脑、脑干、皮质和间脑）中多巴胺 D 受体（DR）的功能（结合能力、G 蛋白激活和表达）在对照组（Wistar）和 Wisket 大鼠中。结果发现，与对照组动物相比，Wisket 大鼠海马体、纹状体和嗅球膜中 DR 介导的 G 蛋白最大激活的能力要高得多，这伴随着 DR 介导的 G 蛋白激活的效力降低。相比之下，在没有改变最大激活的情况下，在前额叶皮层中检测到增强的效力。在饱和结合测定中，在大脑皮质、纹状体中，模型动物中 DR 的最大结合能力较高，而在脑干中则较低，而没有检测到解离常数值的变化。DRmRNA 表达显示出在所研究的区域中更高的水平趋势，而与 Wistar 动物相比，DR 蛋白表达在 Wisket 大鼠的海马体和前额叶皮层中显著升高，但在小脑皮层中没有升高。这项研究证明，Wisket 动物表现出改变的 D 受体表达和功能，这可能与类似精神分裂症的症状有关。
