| Depression is a mental disorder with high incidence, high mortality and high rate of relapse which made huge economic losses to the family and whole society. Hence, the study about the pathogenesis, prevention measures and treatment plan of depression has been drawn wide attention. The occurrence of depression is largely associated with accumulation of stressful life events. The "monoamine hypothesis" of depression, which posits that depression is caused by decreased monoamine in the brain, especially serotonin (5-hydroxytryptamine,5-HT) system function, originated from early clinical observations. Further preclinical and clinical studies found that, in addition to monoamine neurotransmitter, disorder of glutamate (glutamic acid, Glu) and y-aminobutyric acid (gamma-amino-butyric acid, GABA) may be an important reason for the occurrence of depression. Being an important subregion of prefrontal cortex, orbitofrontal cortex (OFC) is closely related to cognition, mood and other advanced brain function. And, it is very sensitive to stress reaction. Disorder of neurotransmitters 5-HT, DA (dopamine, DA), Glu, GABA and their receptors is closely linked to the genesis of depression. The neurotransmitters and their receptors are distributed in the OFC. Hence, study of the relationship between 5-HT1A receptor and neurotransmitters Glu, GABA, DA and their receprors is necessary. Simulating the core of human depression symptom, the chronic unpredictable mild stress (CUMS) depression model set up with rats is widely adopted. This experiment selected the adult male SD rat to establish a CUMS depression model, combining with the OFC area microinjecting drugs and behavior test include adopting sucrose consumption detection, open field test, tail suspension test. Then using high performance liquid chromatography (HPLC) to determine OFC area 5-HT, DA, Glu and GABA levels, and utilizing western blot to detect the expression of Glu NMDA receptor NR2B subunits, AMPA receptor GluR2/3 and DA D1 receptors. In this work, we made a analysis that 5-HT 1A receptor how modulates amino acids and the dopaminergic system within OFC area during CUMS. The results are as follows,1. Compared with normal control group, CUMS rats produced remarkable deprcssioff-like behaviors. At-the same time, in the CFC region Glu level and NMD(?) receptor NR2B subunits expression increased significantly, while AMPA receptor GluR2/3 subunits expression decreased significantly, but it did not change at GABA and 5-HT levels.2. After pharmacological blockade 5-HT1A receptor, normal rats also showed depression-like behaviors, and in the OFC, Glu level and NMDA receptor NR2B subunits expression increased significantly, and AMPA receptor GluR2/3 subunits expression decreased obviously. However, there was no significant difference at GABA and 5-HT levels.3. After microinjected 5-HT1A receptor agonist 8-OH-DPAT, CUMS induced-depressive behaviors are remitted significantly. Meanwhile, Glu level reduced significantly, NMDA receptor NR2B subunits expression quantity decreased markedly, AMPA receptor GluR2/3 subunits expression increased significantly, it did not change significantly at GABA levels.4. Compared to control group, after 21 days stress, model rats showed depressive behaviors. DA concentration and D1 receptor expression decreased obviously in the OFC. Relative to CUMS, microinjecting 5-HT1A agonist 8-OH-DPAT into OFC region can significantly improve CUMS-induced depression. Meanwhile, DA level and D1 receptor expression were significantly elevated.5. After microinjected 5-HT1A receptor antagonist WAY100635, rats exhibited depression-like behaviors. And DA level and D1 receptor expression reduced obviously.6. Microinjected 8-OH-DPAT, combined with SCH23390 (DA D1 receptor antagonist), rats still manifest depressive behaviors. Both DA concentration and Dl receptor expression declined significantly.Taken together, the present data suggested that the mechanism through which CUMS could induce depression-like behaviors, probably is not due to the decrease of 5-HT level within the OFC, but because of excessive release of Glu and NMDA receptor, decreased AMPA receptor, or reduced level of DA and D1 receptor that resulted from that 5-HT could not regulate glutamatergic and dopaminergic neurons or the decrease of 5-HT1A receptor function on glutamatergic and dopaminergic neurons within the OFC during stress. Our data indicated that 5-HT1A receptor in the OFC plays an important role in modulating the synthesis and release of Glu, NMDA and AMPA receptor, DA and D1 receptor during CUMS. When glutamatergic and dopaminergic neurons system is abnormal, antidepressants based on 5-HT may be inefficient or difficult to achieve. This may support for the revised monoamine hypothesis which suggests that depleted monoamine concentrations may play more of a modulatory role to other neurobiological systems, rather than a major direct role in depression. |
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