Relevance Of Agmatine-imidazoline Receptors System To Depression

Psychiatric disorders such as depression, anxiety and schizophrenia are leading causes of disability worldwide, and have a huge societal impact. Depression is a chronic, recurring and potentially life threatening illness that affects up to 20% of the population across the globe. It is one of the top ten causes of morbidity and mortality worldwide based on a survey by the World Health Organization. Despite the prevalence of depression and its considerable impact, knowledge about its pathophysiology is rudimentary compared with knowledge of other common chronic illness. Depression is a heterogeneous disorder with a highly variable course, an inconsistent response to treatment, and no established mechanism. The major theory of depression is the monoamine-deficiency hypothesis, which posits that depression is caused by decreased monoamine function in the brain. All available antidepressant medications have the same core mechanisms of action in promoting monoamine neurotransmitters.Monoamine-based antidepressants remain the first line of therapy for depression, but their long therapeutic delays and low (about 30%) remission rates have encouraged the search for noval more effective agents and therapeutic targets.Several brain regions and circuits regulate emotion, reward and executive function, and dysfunctional changes within these highly interconnected'limbic'regions have been implicated in depression and antidepressant action. Imidazoline receptors (I-R) are distributed in a regional manner, with the highest densities being found in the hippocampus, amygdale and prefrontal cortex (PFC) and these limbic structures are thought to be involved in mood. Evidence is growing that favors the involvement of I-R in the pathophysiology of depression. Agmatine is an endogenous amine that has been proposed as a neurotransmitter and/or neuromodulator in the central nervous system (CNS), which is considered as an endogenous ligand for imidazoline receptors. Based on our research work in the past decade, we proposed that agmatine and imidazoline receptors constitute a novel system of modulating analgesia, tolerance and dependence. Our previous studies and some others abroad demonstrated that exogenous agmatine had antidepressant-like effect in mice and rats.Considering that agmatine has a definite antidepressant activity in several animal models of depression, and that it is an endogenous ligand for imidazoline receptors, the present study sought to investigate the the involvement of imidazoline receptors in the antidepressant effect of agmatine, the relevance of agmatine-imidazoline receptors interaction system to depression and it's possible mechanism.Three animal models, including chronic mild stress(CMS) model in rats, forced swimming test (FST) in mice and rats, tail suspension test(TST) in mice, were used to evaluate the effect of agmatine and the influence of efaroxan or idazoxan, which are the antagonists of I-R on it.In Sprague-Dawley rats, CMS-induced depression was materialized by sucrose consumption test and open field test. Rats receiving CMS for 6 weeks showed behavioral changes that parallel the symptoms of depression, including reduced sucrose intake (anhedonia, reduced ability to experience pleasure from natural rewards) and declined activity in open-field compared with control. Concomitant administration of agmatine (10 mg/kg, i.g.) significantly reversed the depressive-like behaviors in CMS rats. Concomitant pretreatment of idazoxan (1 mg/kg, i.p. an imidazoline receptors antagonist) partly suppressed the antidepressant effect of agmatine. We firstly demonstrated that agmatine has an antidepressant-like effect in CMS-rats, which is related to activation of imidazoline receptors.Treatment of the mice (CD-1) once daily for 3 days with agmatine (10 mg/kg, i.g.) produced significant reductions in the duration of immobility in the forced swim test and the tail suspension test. Concomitant pretreatment of efaroxan (0.1 mg/kg, i.p.) or idazoxan (1 mg/kg, i.p.) significantly suppressed the decrease of immobility time caused by agmatine in the forced swimming test and the tail suspension test. Treatment of the rats once daily for 3 days with agmatine (10 mg/kg, i.g.) produced significant reductions in the duration of immobility in the forced swim test. Concomitant pretreatment of rats with efaroxan (1 mg/kg, i.p.) or idazoxan (1mg/kg, i.p.) significantly suppressed the decrease of immobility time caused by agmatine in the forced swimming test.In order to determine the antidepressant effect of agmatine and the influence of efaroxan and idazoxan on agmatine, we have to exclude the excitatory or inhibitory actions on the central nervous system. Treatment of the mice or rats once daily for 3 days with agmatine (10 mg/kg, i.g.), efaroxan (1 mg/kg, i.p.) or idazoxan (1 mg/kg, i.p.) had no effect on spontaneous motor activity in mice or rats. All these results indicate that agmatine has an antidepressant-like effect in mice and rats.On the other hand, in order to investigate the relevance of agmatine-imidazoline receptors interaction system to depression, the real-time quantitative PCR tequnique and the method of ELISA were used respectively to measure the I1-R mRNA levels and the content of endogenous agmatine in brain regions of hippocampus and prefrontal cortex of normal and CMS-induced depression-like rats. A down-regulation of I1-R mRNA levels was found in hippocampus but not in the prefrontal cortex regions and a decrease of content of endogenous agmatine in the prefrontal cortex regions but not in hippocampus of rats exposed to CMS.Our previous studies in pharmacological depression models indicated that the antidepressant-effect of agmatine was related to the potentiation of central 5-HT system. Another study demonstrated that the antidepressant-like effect of selective serotonin reuptake inhibitors (SSRIs) involved modulation of imidazoline receptors by agmatine. As for the study of possible mechanism, we employed the microdialysis technique in free-moving animals and the high performance liquid chromatography with electrochemical detection (HPLC-ECD) technique to investigate the effect of agmatine on the extracellular level of monoamine neurotransmitters in the brain regions correlated with depression such as the hippocampus and prefrontal regions of the cerebral cortex. Results indicated that, treatment of rats with agmatine (10 mg/kg, i.g.) increased the content of 5-HIAA (5-HT metabolite) in the hippocampus but not in the prefrontal cortex regions, and pretreatment of rats with efaroxan (1 mg/kg, i.p.) suppressed the increase caused by agmatine.In conclusion, agmatine could exert excellent antidepressant effects in multiple animal models of depression, which dependent on its interaction with imidazoline receptors partly. Levels of I1-R mRNA and content of endogenous agmatine was changed in some brain regions of CMS-induced depression-like rats. The mechanisms underlying the antidepressant effect of agmatine-imidazoline receptors system might be related to the potentiation of central serotonergic neurotransmission.