| Depression is a syndrome mainly characterized by low mood and anhedonia.The severely depressed patients often have suicidal thoughts,which is viewed as a serious threat to people’s health and life.The monoamine hypothesis of depression, which is one of the main theories for the pathogenesis of depression, can not fully explain the whole performance of depression. So far, a increasing number of studies have proved that depression happens with various neurotransmitter disorders such as glutamic acid (Glu) andy-aminobutyric acid (GABA), except for monoamine neurotransmitters.Glu is the most important excitatory neurotransmitter in CNS (central nervous system). Abnormalities in glutamatergic systems was consistently identified in depression.There are abundant glutamatergic neurons and gabaergic neurons in the hippocampus. Research showed that chronic stress raised the level of Glu within hippocampus, and NMDA receptors agonist microinjected in hippocampus resulted in depression-like behaviors. Howerver, MK-801, NMDA receptors antagonist, had antidepressant functions.In another word, the Glu level increased by chronic stress within hippocampus and the NMDA receptors activated excessively by high level of Glu, would lead to depression. It was suggested that NMDA receptors and AMPA receptors were involved in the genesis of stress-induced depression, but they performed different functions and influenced each other. Much research suggested the disorder of Glu level and receptors was a critical reason of depression development, and antidepressant functions of monoamine neurotransmitters probably worked by the regulation of glutamatergic neuron system.GABA, γ-aminobutyric acid, the most abundant inhibitory neurotransmitter within CNS, is released at approximately 50% of brain synapses. GABA, the main transmitter of internuncial neuron in hippocampus, regulates monoamine transmitters, peptides and amino acids etc neurotransmitter systems, and is closely related to emotional and mental activities. There have a close relationship between Glu and GABA. GABA is synthesized by the catalysis of glutamate decarboxylase (GAD). GAD levels and GABA syntheis rate are strongly correlated. It was suggested that excessive release of Glu andover-activation of NMDA receptors played a role in stress-induced depression. However, Lower levels of GABA was also contributing to depression. There are three types of GABA receptors, GABAA receptors, GABAB receptors and GABAc receptors. GABAA receptors are widely distributed in the nervous system, and are the principal receptors of GABA receptors in the mammalian brain. Many studies suggested that both synaptic and extrasynaptic GABAA receptors might be involved in the pathophysiology of depression, and different subunits of GABAA receptors performed diverse functions in depression. Though the researchers have distinct results of the expression of GABAA receptors in depression. However, GABAA receptors agonists have the effect of antidepressant and antianxiety. The antidepression effect casued by the activation of GABAA receptors could decrease Glu and increase GABA. It means that the balance of Glu and GABA level is one of the antidepressant ways of GABAA receptors. Furthermore, whole-cell patch-clamp recording found that GABAA receptors could down-regulate glutamate receptors,which suggested that GABAA receptors regulated the effect of the ionotropic glutamate receptors.In summary, GABAA receptors agonists have the effect of antidepressant, and the mechanism relates with the glutamatergic system. The hippocampus is the most widely studied brain area in relation to depression. Glu and GABA both are primary neurotransmitters in hippocampus. The study of glutamatergic system and y-aminobutyric acid system has great significance to reveal the mechanism of stress-induced depression in hippocampus. However, they are still unclear what change will exactly happen on the expression of GABAA receptors within hippocampus in stress-induced depression, and whether GABAA receptors produce antidepressant-like effect via regulating its own expression, GABA level or Glu level, the expression of NMDA receptors and AMPA receptors. In order to solve those problems, we established chronic unpredictable mild stress (CUMS) model of depression. Microinjection of GABAA receptors agonist Muscimol,GABAA receptors antagonist Bicuculline and AMPA receptors antagonist NBQX into hippocampus in rat, we adapted several methods to investigate the way of GABAA receptors antidepressant effect in stress-induced, such as behavior test methods, high-performance liquid chromatography for detecting the level of neurotransmitter within hippocampus, and Western Blot for detecting the expression of GABAA receptors, NMDA receptors and AMPA receptors subunits within hippocampus to investigate the way of GABAA receptors antidepressant effect in stress-induced. The results were shown as followed:1.CUMS significantly induced the depressive-like behaviors in rats, increased the level of Glu, decreased the level of GABA and significantly increased the ratio of Glu/GABA. The expression of GABAA receptors, NMDA receptors’subunits NR2B and AMPA receptors subunits (GluR2/3) decreased significantly within hippocampus in comparison with the control group.2.GABAA receptors agonist Muscimol in hippocampus effectively restrained the depression-like behaviors induced by CUMS, and the level of GABA within hippocampus increased significantly. The expression of GABAA receptors showed no significant change.Microinjection of GABAA receptors antagonist Bicuculline into hippocampus caused animal depressive-like behaviors and the content of GABA significantly decreased. The expression of GABAA receptors indicated no significance3.Microinjection of GABAA receptors agonist Muscimol into hippocampus decreased the level of Glu, but not significant. The expression of NMDA receptors subunits (NR2B) and AMPA receptors subunits (GluR2/3) increased significantly, while hippocampal microinjecting GABAA receptors antagonist Bicuculline increased the level of Glu and significantly decreased the expression of NMDA receptors subunits (NR2B) and AMPA receptors subunits (GluR2/3).4.Microinjection of GABAA receptors agonist Muscimol into hippocampus decreased the ratio of Glu/GABA, while hippocampal microinjecting GABAA receptors antagonist Bicuculline increased the ratio of Glu/GABA.5.AMPA receptors antagonist NBQX weakened the antidepressant effect of GABAA receptors agonist Muscimol.These results suggested that the dysfunction of glutamatergic system, andy-aminobutyric acid system as well as the disequilibrium between glutamatergic system and y-aminobutyric acid system in hippocampus, could induced the depressive-like behaviors. CUMS induced the depressive-like behaviors via decreasing the level of GABA and the expression of GABAA receptors, increasing the level of Glu and decreasing the expression of NMDA receptors’subunits NR2B and AMPA receptors’ subunits GluR2/3. GABAA receptors agonist Muscimol increased the level of GABA, decreased the ratio of Glu/GABA and increased the expression of NMDA receptors subunits (NR2B) and AMPA receptors subunits (GluR2/3) in hippocampus. Above all, GABAA receptors agonist Muscimol microinjected into hippocampus exerted antidepressant effect via regulating the balance of glutamatergic system and γ-aminobutyric acid system. The antidepressant effect of GABAA receptors agonist Muscimol was mediated by AMPA receptor partially... |
PDF Full Text Request