| Objective: Obsessive Compulsive Disorder(OCD)is a mental disorder with obsessive-compulsive symptoms as the main clinical phase.Obsessive-compulsive disorder is the fourth most common psychiatric disease after phobia,substance abuse and major depression.Epidemiological surveys show that the prevalence of obsessive-compulsive disorder in people of different races is about 1.1%-3.3%.Obsessive-compulsive disorder is characterized by the presence of forced thinking and/or compulsive behavior.Forced thinking is a repetitive,continuous,intrusive,undesired thought,desire,and image;compulsive behavior refers to the mental activity that is driven by forced thinking or repeated according to the rigid rules that must be observed.The fifth edition of the Diagnostic and Statistical Manual of Mental Disorders(DSM-V)treats compulsion and related disorders as a type of disease independent of anxiety and as an independent chapter.In recent years,more and more studies have found that the glutamate system may be related to the onset of obsessive-compulsive disorder.Clinical studies have found that glutamate concentrations in cerebrospinal fluid in patients with obsessive-compulsive disorder who are not treated are elevated and are associated with the severity of the disease.D-cycloserine is N-methyl-D-aspartate(NMDA)glutamate receptor partial agonist,which can enhance the exposure therapy and improve OCD symptoms.In this study,we aimed to construct the rat OCD model and to explore the NMDA receptor and subunits in the hippocampus through neurophysiological,neurobehavioral,biochemical,molecular biology and histopathological techniques and to analyze the relationship between receptor activation and D-serine,glutamate,glycine content.By using NMDA receptors and subunit selective antagonists changes in behavioral and biological indicators,the function of each of the NMDA receptor subtypes and their role in the striatum was examined,and the pathogenesis of obsessive-compulsive disorder from the NMDA receptor subtypes in the hippocampus was explored.Our study also provides new targets for the treatment of obsessive-compulsive disorder.New therapeutic drugs and pharmacological mechanisms of obsessive-compulsive disorder were discovered by using different doses and different time DCS on the symptoms of obsessive-compulsive disorder and the corresponding biological indicators.In this study,we explored the effects of glutamate-related drugs on the compulsive behavior of quincloline(QNP)-induced compulsive behavior bodel rats and its underlying mechanisms to deepen understanding about relationships between obsessive-compulsive disorder and glutamate.Methods: 1.We selected patients with SSRIs treatment-resistant obsessive who were treated at Shengjing Hospital of China Medical University from July to May 2016.A total of 51 cases met the inclusion criteria and did not meet the exclusion criteria.These patients were randomly divided into experimental group and control group.Patients in the experimental group were treated with Lamotrigine enhancement therapy for 8 weeks.After1 week of treatment,the dose was adjusted according to the patient's condition and signs.The control group was given a placebo treatment.The study was reviewed by the Ethics Committee of China Medical University,and all subjects signed informed consent.Y-BOCS and HAMD were used to assess the severity of obsessive-compulsive disorder and anxiety symptoms in patients with obsessive-compulsive disorder before treatment and at 2,4,and 8 weeks of treatment.The efficacy of the two groups of patients was compared.2.This study constructed a QNP-induced rat model of obsessive-compulsive disorder.To test the effects of NMDAR-related drugs NVP-AAMO77,Ro25-6981,and D-Cycloserin on the behavior of obsessive-compulsive rats,we performed a series of tests for anxiety and compulsive behavior including elevated O-maze experiments,open field experiments,and marble burying test.At the same time,we compared the effects of three drugs on anxiety and obsessive behavior in rats with obsessive-compulsive disorder.3.We examined and compared the effects of three NMDAR-related drugs on hippocampal neurotransmitters(including glutamate,glycine,and serine)in compulsive behavior model rats.To further elucidate the molecular effects of NVP-AAMO77,Ro25-6981 and D-Cycloserin in QNP-induced obsessive-compulsive disorder,we evaluated and compared the expression levels of NMDAR 2A and NMDAR 2B in rat hippocampus by immunohistochemistry and western blot.Results: 1.In the control group,there were 10 males and 15 females;the average age was(35.32 ± 2.46)years old.There were 11 males and 15 females in the experimental group;the average age was(34.04 ± 21.87)years old.There was no significant difference in the Ycale-Brown score and the HAMA score between the two groups before treatment(P >0.05).There were significant differences in Ycale-Brown scores and HAMA scores between the two groups before and after treatment(P < 0.05).In addition,there was a significant difference in Ycale-Brown score and HAMA score between the two groups(P <0.05),indicating that Lamotrigine drugs are effective in treating SSRIs treatment-resistant obsessive.2.Competitive N-methyl-D-aspartate glutamate receptor(NMDAR)antagonists NVP-AAMO77(5 mg / kg)and Ro25-6981(5 mg / kg)significantly inhibited rat Anxiety and compulsive behavior.And all doses of D-cycloserine showed significant inhibition of anxiety and marble burial behavior.3.Compared with the saline-treated group,the levels of glutamate(Glu)in the hippocampus of the NVP-AAMO77 and D-cycloserine-treated groups reflected changes in glutamatergic neurotransmission,and their levels were significantly reduced.The levels of other amino acids are not affected.Furthermore,NVP-AAMO77 significantly reduced the expression of the NR2 A subunit of NMDAR,Ro25-6981 inhibited the level of the NR2 B subunit of NMDAR,while D-serine reduced the NR2 A and NR2 B subunits of NMDAR.Conclusions: 1.By comparing the therapeutic effects of the two groups of patients,the patients in the experimental group were treated with Lamotrigine enhancement therapy for8 weeks,and the control group was given placebo.We found that Lamotrigine enhancement therapy was effective in treating SSRIs treatment-resistant obsessive-compulsive disorder.2.Through a series of behavioral tests,our results showed that NMDAR-related drugs NVP-AAMO77,Ro25-6981,and D-Cycloserin could inhibit anxiety and compulsive behavior in rats with compulsive behavior.3.NMDAR-related drugs NVP-AAMO77,Ro25-6981,and D-Cycloserin could significantly reduce glutamate levels in the hippocampus of rats with compulsive behavior and significantly inhibited the NR2 A or NR2 B subunit of NMDAR,suggesting that D-cycloserine,NVP-AAMO77 and Ro25-6981 may be effective drugs for the treatment of obsessive-compulsive disorder,possibly by inhibiting NR2 A or NR2 B levels of NMDAR. |
PDF Full Text Request