The Role Of 5-HT_2A Receptor And Opioid Peptide In The Frontal Lobe Of Chronic Stress-induced Depression-like Behavior And Its Regulation Of Neural Plasticity

Major depression is common illnesses with considerable morbidity and significant mortality,which will be the foremost contributor to the worldwide burden of disease by 2030.Despite extensive research,the neurobiology of depression remains poorly understood.Several hypothesis on pathogenesis of depression were proposed.However,all the hypothesis were based on single factor and can't explain all the mechanisms underlying depression sufficiently.The monoamine hypothesis of depression,especially serotonin?5-HT?hypothesis,was the most accepted by the scientific community,and selective 5-HT reuptake inhibitors?SSRIs?remain the first choice in antidepressant drug treatment.Although monoamine-based antidepressants could increase the 5-HT level in the synaptic cleft,many drugs have delayed and side effects and approximately 30%?40%of patients may not respond to drug therapy.Nowadays,the role of 5-HT in the depression,particularly the role of various 5-HT receptor,and whether changes in brain 5-HT function are causally linked to the symptoms of depression are undefined.The 5-HT_2A receptor is abundant in the prefrontal cortex?PFC?and pharmacological studies have shown that 5-HT_2A receptor modulation is associated with depressive-like behavior.However,the role of 5-HT_2A receptor in the development of stress-induced depression remains unclear.Seventy-five per cent of the beneficial action of antidepressants have been ascribed to a placebo response.Postmortem examination reveals a decreased concentration of?-endorphin levels in several brain regions of suicides and an increased density of ?opioid receptor in the frontal cortex.It was reported that plasma ?-endorphins levels were found to be elevated in patients after antidepressant treatment or receiving electroconvulsive shock?ECS?for the treatment of depression.Systemical administration or intracerebroventricular injection of 8 and ? opioid receptors agonist produced a significant antidepressant-like effect.These results suggested that the endogenous opioid system may be directly involved in the pathogenesis of depression.However,the role and mechanisms of ? and ? opioid receptors in the central nervous system?CNS?in stress-induced depression remains limited understand.Chronic stress can increase risk of depression in humans and increase propensity to participate in drug-seeking behavior in humans and rodents.Chronic stress induced the change of monoamine system,unbalance of neuroendocrine system and appearance of inflammation,as well as the significant neural plasticity change.Over 90%of all excitatory synapses that occur in the CNS are sitting on dendritic spines which are cellular substrates of brain connectivity and the major sites of information processing in the brain.It is widely accepted that the regulation of dendritic spine number,size and shape is of importance to the plasticity of synapses as well as psychiatric disorder.The formation of the dendritic spines are commonly dysregulated or disrupted in chronically stressed animals,accompanied by depressive-like behaviors.Recovery of chronic stress-induced decrease in spine density and destruction in synapse function can ameliorate depressive-like behaviors.Therefore,study on dendritic spines is one of the basic tasks to unravel the mechanism of depression.Kalirin-7?Kal7?plays a crucial role in regulating synaptic plasticity and maintaining dendritic spines in mature neurons,which located in the postsynaptic density?PSD?and interacts with glutamate receptor and PSD95.In cultured cortical neurons,activation of 5-HT_2A receptor induces a transient increase in dendritic spine size via Kal7 signaling.? receptor agonists have been shown to increase expression of brain-derived neurotrophic factor?BDNF?mRNA,suggesting that opioids regulate the neuroplasticity.However,it is unclear whether orbitofrontal 5-HT_2A receptors and opioid receptors affect Kal7 level and dendritic spines in rats with depressive-like behaviors induced by chronic unpredictable mild stress?CUMS?.As a major subdivision of the PFC,the orbitofrontal cortex?OFC?participates directly in emotional and cognitive processing,adaptive behaviors and other stress-sensitive functions.Neuroimaging and postmortem studies show that patients with major depression have reduced volume of the OFC and the density of pyramidal neurons in the OFC.Lesion of the OFC heightened negative emotion.In the OFC,spine density declines after chronic corticosteroid exposure and fails to recover after a washout period,despite apical dendritic hypertrophy in the OFC after chronic restraint stress.Forced swimming stress induced a decrease of spine density.These results suggest that both the structural and functional plasticity of the OFC play an important role in the progression of stress-induced depression.However,it is poorly understood how chronic stress effect on neural plasticity of the OFC.It shows that neuroplasticity hypothesis may the integration platform for other hypotheses of depression.It is maybe an efficient strategy to recovery of decrease in spine density and destruction in synapse function for depression treatment.The study on the relationship of neurotransmitters and neuroplasticity and mechanisms underlying depression may provide new insights for understanding the pathogenesis of depression and developing more efficient therapy.Therefore,the aim of this study was to investigate the role of orbitofrontal 5-HT_2A receptors and opioid receptors in depressive-like behaviors and their associations with Kal7 and dendritic spines using chronic unpredictable mild stress?CUMS?.In the present study,we established a CUMS rat model,and detected the concentration of 5-HT and opioids in the OFC by high performance liquid chromatography with fluorescence detection or enzyme linked immunosorbent assay.Then the role of 5-HT_2AR,? and ? opioid receptors agonist and antagonist by infusions into the OFC on depressive-like behaviors were investigated.The level of 5-HT_2AR,Kal7 and PSD95 were detected by western blot analysis,meanwhile dendrites and spines in the OFC pyramidal neurons were analyzes after Golgi-Cox stained.Results:1)21-day CUMS induced depressive-like behaviors in rats including decreased body weight and locomotor activity,loss of interest and behavioral despair.The level of the left OFC did not significantly decreased,while dopamine level significantly declined in the CUMS rats.2)The level of 5-HT_2AR in the left OFC did not change compared to controls.Injection of 5-HT_2A/2C receptor agonist DOI into the OFC produced depressive-like activities similar to those observed in rats exposed to CUMS.The 5-HT_2A receptor antagonist Ket reversed the depressive-like activities induced by CUMS.3)CUMS induced the significant decline of the enkephalin level in the left OFC in comparison with controls group,but not?-endorphin level.The 8 opioid receptors agonist SNC80 reversed the depressive-like activities induced by CUMS,while ?opioid receptors agonist EM-1 partly ameliorate those behaviors.8 opioid receptors antagonist Nal and ? opioid receptors antagonist CTAP had no effects on behaviors in the control group.4)The level of 5-HT and DA were increased when pretreatment with SNC80 in the CUMS rats rather than EM-1treament.No differences in NA levels in all groups were found.Nal and CTAP infusion into the OFC in the control rats did not alter the monoamine levels.5)CUMS-induced or DOI-induced depressive-like behaviors were accompanied by decreased expression of Kal7 as well as decreased dendritic spine density in the OFC.The spine size,total dendritic length and number of dendritic branches were unaffected by CUMS or drug infusions.Ket and SNC80 treatment reversed CUMS-mediated decrease in spine density.Conclusions:1)CUMS did not alter the levels of 5-HT in the OFC,but rather resulted in depressive-like behaviors through activation of the orbital 5-HT_2A receptor in rats.2)CUMS induced the significant decrease of the enkephalin level in the OFC,while activation of the orbital opioid receptors,especially,ameliorated depressive-like behaviors.3)Activation of ? opioid receptors could reverse CUMS-induced behavioral abnormalities through increasing 5-HT and DA levels,while the role of ? opioid receptors maybe through the other way.4)Depressive-like behaviors is closely associated with Kal7 levels and spine density.Changes of Kal7 levels and spine density were concerned with the effect of 5-HT_2A receptors or opioid receptors.In summarized,21-day CUMS induced depressive-like behaviors,and decreased the levels of DA and enkephalin,but not affected the levels of orbitofrontal 5-HT or 5-HT_2A receptors.Inhibition of 5-HT_2A receptors or activation of opioid receptors reversed CUMS-induced depressive-like behaviors,and recovered the decline of Kal7 and PSD95 levels and decrease of spine density.These results indicated the orbital monoamine transmitters?5-HT and DA?and opioids are involved in stress-induced depression and structural plasticity,suggesting an important role of Kal7 in regulation of dendritic spine density in depression.