Effect Of 5 - HT1B Receptor In Hippocampal CA1 Region Of Stress - Induced Depression And Its Mechanism

Pathogenesis and treatment strategies for depression have been highly concerned in the field of neuroscience and medicine, and they have proposed a variety of theories. Earlier monoamine neurotransmitters dysregulation hypothesis played an important role in the pathogenesis of depression, and clinical treatment of depression based on serotonin (5-hydroxytryptamine,5-HT) also has gained good results. However, with further research, more research proved glutamate receptors also play an important role in the genesis of depression, and5-HT is likely involved in depression through the regulation of glutamatergic synapses.Researches always used to focusing on5-HT1A receptors, followed by5-HT7,5-HT2, and5-HT3receptors. And5-HT1B receptors (5-hydroxytryptamine receptor1B,5-HT1BR) got little attention. Studies have shown that5-HT1BR closely with drug addiction, aggression and so on. Recent studies have also found that5-HT1BR is a potential target in the pathology of depression.Hippocampus is one of the important brain areas closely related to emotion, mood, as we know, it is involved in stress response as well. Studies suggested that there are serotoningic neurons in the hippocampus projection, which include5-HT1BR. Chronic stress can cause structural and functional changes in the hippocampus. And studies have shown that5-HT1BR is involved in depression, however, whether hippocampal5-HT1BR plays any role in stress-induced depression and whether the role works via regulating the release of5-HT and Glu are still not clear. In order to solve this problem, we established chronic unpredictable mild stress (CUMS) model of depression. Using the pharmacology approach by microinjection of5-HT1BR agonist CP93129and antagonist GR55562to hippocampal CA1rat, then we measured body weight of rats and utilized behavior test methods such as sucrose preference test and tail suspension test for detecting behavioral changes of rats, and utilized high-performance liquid chromatography for detecting the level of neurotransmitter in the hippocampus, and Western Blot for detecting the expression of NMDAR and AMPAR key subunits in the hippocampus. The results showed as following.1. Compared to the control group, the CUMS group showed significant depressive-like behaviors. In the CUMS group, the weight variation, sucrose preference variation decreased significantly and tail suspension immobility time increased significantly (n=10, P<0.01). The concentration of Glu in hippocampus increased significantly (n=8, P<0.01), but hippocampal5-HT concentration didn’t change significantly (n=9, P>0.05), and the expression of NMDA receptor NR2B subunit, AMPA receptor GluR2/3subunit and PSD95decreased significantly (n=6, P<0.01).2. Micro injection of5-HT1BR agonist CP93129had no effect on the normal behavioral manifestations (n=6, P>0.05). But compared with CUMS group, hippocampal microinjection of5-HT1BR agonist CP93129was able to improve the CUMS-induced depression-like behaviors significantly. When rats of the CUMS group were microinjected CP93129, their weight variation, sucrose preference variation elevated significantly (n=8, P<0.01, P<0.01), and tail suspension immobility time decreased significantly (n=8, P<0.01); the concentration of Glu in hippocampus decreased significantly (n=8, P<0.01), whereas hippocampal5-HT concentration didn’t change significantly (n=8, P>0.05); the expression of NMDA receptor NR2B subunit and AMPA receptor GluR2/3subunit increased significantly (n=6, P<0.01), and the expression of PSD95expression increased (n=6, P<0.05).3. Microinjection of5-HT1BR antagonist GR55562had no effect on the normal behavioral manifestations (n=6, P>0.05). But compared with CUMS group, hippocampal microinjection of5-HT1BR antagonist GR55562can also improve CUMS-induced depression-like behaviors significantly. When rats of the CUMS group were microinjected GR55562, their weight variation, sucrose preference variation elevated significantly (n=9, P<0.05, P<0.01), and tail suspension immobility time decreased (n=9, P<0.05); the concentration of Glu in hippocampus did not change significantly (n=8, P>0.05), while hippocampal5-HT concentration increased significantly (n=8, P<0.01); the expression of NMDA receptor NR2B subunit and AMPA receptor GluR2/3subunit increased significantly (n=6, P<0.01), and the expression of PSD95increased significantly (n=6, P<0.01).These results suggested that5-HT1B receptor plays an important role in stress-induced depression-like behavior regulation. The antidepressant effect of5-HT1BR agonist CP93129is achieved by reducing the Glu level and improving the expression of NMDA receptor NR2B subunit, AMPA receptor GluR2/3subunits and PSD95significantly, in other words, through the regulation of glutamatergic synapses directly. However,5-HT1BR antagonist GR55562can elevate hippocampal5-HT levels, and increase the expression of glutamate receptors NMDA receptor NR2B subunits, AMPA receptor GluR2/3subunits and PSD95significantly, so that stress-induced depression-like behavior improved. Therefore,5-HT1B receptors in hippocampal CA1are involved in the genesis of stress-induced depression, and the mechanism relates with the interaction between the5-HT system and glutamatergic system.