Dysfunction In Reward System Of CUMS Rat Model Of Depression And Antidepressive Effect Of China Medicine VS SSRIs

Major depressive disorder(MDD) is a very common mental disease, characterizedas the continued depressed mood. The core symptoms of MDD are anhedonia and lossof motivation. The course of MDD is usually very long and easily to relapse. Thepatients of MDD have very high suicide rate. It seriously threats the people’s life healthand life quality. The pathogenesis of MDD is very complicated and remains uncoverednowadays. Therefore, it is of great significance to perform a thorough investigation onMDD. In this work, we explored the change of the neurological biochemistry in thereward system before and after taken medicine in deferent period of time.Part Ⅰ: Research of the dysfunction of dopaminereceptor2and dopamine receptor3in the dopamine rewardsystemExperiment1: establishment of chronic unpredictablemild stress rat modelObjective: Rat model of depression is a very important means for the researchwork. A stable and reliable model is the necessary for good results. Our research usedchronic unpredictable mild stress combined with Solitary support to establish a stableand reliable model of depression to lay a solid foundation for the further research. Methods:16adult Sprague-Dawley (SD) rats were randomly divided into thecontrol group and the model group. We used long-term variety of chronic unpredictablemild stress combine to solitary support to establish the rat model of depression. We usedvariety of chronic unpredictable mild stress combine to solitary support for21days toestablish the rat model of depression. The fluid consumption test, the forced swimmingtest and the body weight were compared before and after the process of stress. Theseresults were used to investigate the degree of anhedonia and behavioral despair. Afterthe accomplishment of the model, we used HPLC-MS to analysis changes ofmonoamine neurotransmitter of DA, DOPAC, HVA,5-HT,5-HIAA in the prefrontallobe, hippocampus and nucleus accumbens to verify the validity of the model.Results:1. The results of behavioral experiments: Compared with rats in control group, thesucrose preference index of rats after stress procedure in model group decreasedsignificantly; the swimming test static time of the model group rats extended greatly;the growth rate of rats in model group was significantly less than those in the controlgroup.2. The HPLC-MS analysis results showed: Significantly reduction of DA, DOPAC,HVA,5-HT,5-HIAA in the prefrontal lobe, hippocampus and nucleus accumbens wasfounded in model group.Conclusion:1. The rat model of depression of chronic unpredictable mild stress combinedwith solitary support can imitate the core symptoms of depression. Afterthe model was established, the index of anhedonia, behavioral despair andweight loss changed dramatically. The changes of monoamineneurotransmitter of DA, DOPAC, HVA,5-HT,5-HIAA were accord withthe current knowledge on the neurological biochemistry change indepression. Our rat model of depression was reliable, repeated easily, stableand prolonged enough for the further research. Experiment2: Slective serotonin (5-HT) reuptakeinhibitors (SSRIs) has influence on the reward system in therat model of depressionObjective: The core symptom of depression anhedonia is a direct reflection ofdysfunction of the reward system. We used rat model of depression to explore theevidence of changes of the dopamine receptor2(D2DR) and dopamine receptor3(D3DR) in the important area of the reward sysmem. We want to estimate the exactlychanges of D2DR and D3DR after usage of antidepressant drug’s of dopamine and itmetabolites, D2DR、D3DR, to get a further understand of the act of SSRIs on the rewardsystem.Methods: The depressed rats made according to experiment1were randomlydivided into4groups, namely the acutely controlled saline group, the chronic controlledsaline group, the acutely citaloplam group and the chronic citalopram group. We alsoset up a control group where the rats were raised normally and the model group thatonly received stress intervention but no medicine. The fluid consumption test, theforced swimming test and the body weight were all accomplished before and after thestress interventions and the medicine interventions. HPLC-MS and Western Blottingmethod were used to analysis changes of monoamine neurotransmitter of DA, DOPAC,HVA,5-HT,5-HIAA and changes of D2DR、D3DR in the prefrontal lobe, hippocampusand nucleus accumbens to verify the act of SSRIs on the reward system after acutelyand chronic use of drugs.Results:1. The chronic group showed significantly behavioral promotion with the distinctlypromoted sucrose preference index; the distinctly shortened swimming test static timeand the significantly increased growth body weight rate of rats in the chronic controlcitaloplam group. Such promotion effect was not discovered in saline group or theacutely citaloplam group.2. The DA in nucleus accumbens, the DOPAC in hippocampus and the5-HTincreased remarkably after the acutely use of citaloplam, but this increase was notdiscovered in the acutely saline group. The DA, DOPAC, HVA,5-HT,5-HIAA in allthree area increased remarkably after chronic use of citaoplam, but this effect was notobserved in the chronic saline group. 3. After the stress interventions, the model rats’ D2DR、D3DR expression decreasedsignificantly compared with the control group in all areas of the prefrontal lobe,hippocampus and nucleus accumbens. There were significantly increase of D2DR、D3DR expression in all three areas in the acutely group of citaloplam. However, thisphenomenon was not observed in the saline group. The D2DR expression increasedmore in chronic use of citaloplam, but D3DR expression were decreased after chronicuse of citaloplam vs. saline. The D2DR、D3DR expression in all three area were notrecovered as controlled group.Conclusion:1. The rat model of depression had dysfunction in reward system as the decrease inthe dopamine and its metabolites and the decrease of expression of D2DR、D3DR.2. The expression of D3DR had a transitory increase after acutely use of citaloplam,but decreased significantly after chronic use of citaloplam, indicated that citaloplam hada kind of inhibition on the reward system. Although the expression of D2DR wereincreased, but did not reach the normal level, indicated that the reward system was notrecovery after use of drugs.Part Ⅱ: The Chaihu-jia-longgu-muli decoction (CJLMD)’sact as an antidepressantObjective: The Chinese traditional medicine is the treasure of China history. But itis not very popular in today because of its complex mechanism. We used the rat modelto explore the antidepressive act of CJLMD and the mechanism of it by comparing itseffect with those of citaloplam.Methods: The depressed rats made accord to experiment1were randomlydivided into6groups, namely the acutely controlled saline group, the chronic controlledsaline group, the acutely citaloplam group, the chronic citalopram group, the acutelyCJLMD group and the chronic CJLMD group. The fluid consumption test, the forcedswimming test and body weight were all accomplished before and after the medicineintervention. HPLC-MS and Western Blotting method were used to analysis change ofin concentration of monoamine neurotransmitter of DA, DOPAC, HVA,5-HT,5-HIAA and change of concentration of D2DR、D3DR in the prefrontal lobe, hippocampus andnucleus accumbens to verify the act of SSRIs on the reward system after acutely andchronic use of drugs.Results:1. The CJLMD group had the same antidepressive acts as the citalopram groupafter chronic use of drugs in the changes of depressive behaviors of sucrose preferenceindex and the growth rate of body weight, and had even more distinctly shorten time inswimming test static time than the citalopram group.2. The concentration of DA, DOPAC, HVA,5-HT,5-HIAA of all three area in theCJLMD group increased weaker than the citaloplam group in all aspects, but increasedmore the saline group.3. There were same trend of changes in the expression of D2DR、D3DR as thecitaloplam group in all three area but more weaker the citaloplam group.Conclusion:1. From the point of view of the depressive behaviors change of rats, the CJLMDhad more valid antidepressive act than the citalopram group especially in the aspect ofswimming test static time. We postulated that CJLMD can cure behavioral despair andloss of motivation which are the results of damaged reward system. The resultsindicated that CJLMD had a protectable act on reward system.2. Comparing with citaloplam, we postulated that CJLMD had a similarantidepressive act like citaloplam, but is more weaker in the aspect of change inmonoamine neurotransmitter and D2DR、 D3DR. According to the better behaviorchange we postulated that CJLMD might had other mechanisms of antidepressive actother than SSRIs, such as protection the reward system. We will address this issue in thefuture.