缰核介导P物质受体拮抗剂抗抑郁作用及机制的研究
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摘要
抑郁症因其发病率的逐年上升及其造成的社会危害,已经成为当今社会生物学及医学界的研究热点,然而传统的抗抑郁药由于其副作用较大限制其在临床的应用。P物质受体拮抗剂(SPA)作为新型的抗抑郁药越来越受到人们的重视,但对于其作用机制还不完全清楚。缰核是位于上丘脑,联系边缘前脑及脑干的一个重要的神经核团,参与了机体应激、睡眠及情绪等多种生理功能的调节,并且与情绪有关的中缝背核(DRN)、海马及下丘脑室旁核等多个中枢核团具有密切的纤维联系,在抑郁症发病及治疗机制中可能具有重要的作用。本课题主要从行为学、电生理学及生物化学等多角度证明了LHb损毁可通过提高DRN内5-HT水平、抑制下丘脑-垂体-肾上腺皮质(HPA)轴的活动改善抑郁症大鼠的抑郁行为。SPA可通过抑制LHb神经元来提高DRN神经元的兴奋性,进而增加抑郁症大鼠脑内5-HT水平,来实现其抗抑郁作用。
At present, the morbidity of depressive disorder is increasing. According to the specialist, the incidence rate of depressive disorder will be the second among all disease at 2020. Clinically effective antidepressant drugs are thought to exert therapeutic effects by facilitating serotonin (5-HT) function suggesting that 5-HT depletion plays a key role in the pathogenesis of depression. A large number of 5-HT cells were observed in the dorsal raphe nucleus (DRN), and their terminals are widely distributed throughout the forebrain. DRN lesions could decrease the level of 5-HT. This result means that the activity changes of DRN plays a key role in the development of depression. At present, the study of depression are all focus on the action of neurotransmitter, seldom on the site of action. The habenular nucleus (Hb), especially, lateral habenula (LHb) is the major relay station between forebrain and midbrain raphe. It is involved in the regulation of many physiological functions. The LHb has a relay function, conveying limbic forebrain input to the DRN structure and exerts a functional inhibition on bioelectrical activity of DRN neurons. Some studies showed that the activity of DRN neurons was changed by stimulating the Hb electrically. At the pesent stage, the treatment of depression was mainly focus on the drugs which could increase 5-HT level in brain, such as serotonin reuptake inhibitor and monoamine oxidase inhibitor. But these drugs have much side effects, so the scientists are finding another drug which has little side effect. Substance P (SP) is a kind of neuropeptide which has closely relationship with depression and anxiety disorders. And it exert its effects by binding to Neurokinin 1 (NK-1) receptor. The SP antagonist and SP receptor are mainly expressed these encephalic regions which have relationship with stress, fear and affection, such as amygdala, hippocampus, hypothalamus and forefrontal cortex. And stress could induce changes of SP in these regions. Administration SP to central nervous system could produce behavior of fear. Stress is an important factor which induce depressive disorder. The gene damage of NK1 receptor and treated by SPA could decrease response of anxous and stress of mice. And the most obviously characteristic of SPA action is no side effects which traditional antidepressant have, such as conscious-sedation, motor neuron damage and sexual disturbance. SPA will be a new antidepressant and will be applicated in clinical. This study will to improve the key role of LHb in the development of depressive disorder, and it is LHb which mediated the antidepressive effect of SPA. To improve the LHb is the site of action of SPA in central nervous system.The result of this stuy showed:
(1)The immobile time of depressed rats which induced by chronic mild stress (CMS) were increased and the climbing time were deacreased (P<0.001). The activities of CMS rats were decreased obviously compared with that of before stress; The immobile time of depressed rats which induced by clomipramine (CLI) were longer than that of normal rats and the climbing time were shorter than that of normal rats (P<0.001). The activity of CLI rats were lower than that of normal rats. After LHb lesions, the immobile time of CMS rats and CLI rats were all decreased (P<0.05) and the climbing time were all increased (P<0.05). Inhibit LHb by lidocaine also could induce the decreased of immobile time (P<0.001) and the increased of climbing time (P<0.05) of CMS rats. The result were similar with LHb lesions.
(2)The result of radioimmunodetection showed that the level of blood cortisol of CMS rats were obviously higher than that of normal rats (P<0.01). LHb lesions could induce the decreased of blood cortisol (P<0.05).
(3)The result of immunohistochemistry showed that the expression of corticotrophic releasing hormone (CRH) were higher than that of normal rats in periventricular nucleus (PVN). The number of CRH cell were increased in PVN of CMS rats.
(4)The extracellular 5-HT level in DRN of CMS rats and CLI rats were lower than that of normal rats detected by microdialysis (P<0.05). The extracellular 5-HT level in DRN were increased after LHb lesions both in CMS rats and in CLI rats (P<0.05). The extracellular 5-HT level in DRN were not changed in sham rats (P>0.05).
(5)Local application of lidocaine into LHb induced a significant increase in the extracellular 5-HT level in DRN of CLI group (from 98.2±4.3% of baseline to 170.4±18.1% of baseline, P<0.05). Glu 1.8_g/kg significantly decreased extracellular 5-HT levels in DRN of CLI group (from 98.2±4.3% of baseline to 52.9±8.0% of baseline, P<0.001).
(6)There are no changes in FST both in CMS rats and in CLI rats after administrated of SP (0.3μg) into LHb (P>0.05). The immobile time were decreased (P<0.01) and the climbing time increased (P<0.05) after administrated SPA (0.3μg) into LHb both in CMS rats and in CLI rats. But there were no changes after adminstrated SPA/SP into LHb (P>0.05).
(7)The result of extracelluar firing showed that the firing rate of serotonergic neurons in DRN were increased after local microinjection of SPA into LHb (P<0.01). And the firing rate of serotonergic neurons in DRN were decreased after local microinjection of SP into LHb (P<0.01).
(8)SPA could decreased the firing rate of LHb neurons in slices (P<0.001), and SP could increased the firing rate of LHb neurons in slices (P<0.05).
(9)The extracellular 5-HT level in DRN were increased 28% compared with that of before administration of SPA into LHb in CMS rats (P<0.05). The extracellular 5-HT level in DRN were increased 30% compared with that of before administration of SPA into LHb in CLI rats (P<0.05). Local microinjection of SPA into LHb could induce the increasing of extracellular 5-HT in DRN both in CMS rats and in CLI rats. According to these results, we can draw the below conclusions:
(1)The depressed animal model of CMS and CLI were validity, reliability and utility. And they can be used to study depressive disorder.
(2)LHb lesions could improve the behavioral response in depressed rats via increasing the serotonin level in dorsal raphe nucleus and inhibition hypothalamic-pituitary-adrenocortical axis. From our studies, we conclude that function of the LHb is a crucial factor in the pathogenesis and therapy of depression.
(3)LHb is the site of action of SPA in central nervous system. SPA could inhibit the activity of LHb neurons. The antidepressive effect of SPA were exerted by directly inhibit LHb to increase extracellular 5-HT level in brain.
At present, the morbidity of depressive disorder is increasing. According to the specialist, the incidence rate of depressive disorder will be the second among all disease at 2020. Clinically effective antidepressant drugs are thought to exert therapeutic effects by facilitating serotonin (5-HT) function suggesting that 5-HT depletion plays a key role in the pathogenesis of depression. A large number of 5-HT cells were observed in the dorsal raphe nucleus (DRN), and their terminals are widely distributed throughout the forebrain. DRN lesions could decrease the level of 5-HT. This result means that the activity changes of DRN plays a key role in the development of depression. At present, the study of depression are all focus on the action of neurotransmitter, seldom on the site of action. The habenular nucleus (Hb), especially, lateral habenula (LHb) is the major relay station between forebrain and midbrain raphe. It is involved in the regulation of many physiological functions. The LHb has a relay function, conveying limbic forebrain input to the DRN structure and exerts a functional inhibition on bioelectrical activity of DRN neurons. Some studies showed that the activity of DRN neurons was changed by stimulating the Hb electrically. At the pesent stage, the treatment of depression was mainly focus on the drugs which could increase 5-HT level in brain, such as serotonin reuptake inhibitor and monoamine oxidase inhibitor. But these drugs have much side effects, so the scientists are finding another drug which has little side effect. Substance P (SP) is a kind of neuropeptide which has closely relationship with depression and anxiety disorders. And it exert its effects by binding to Neurokinin 1 (NK-1) receptor. The SP antagonist and SP receptor are mainly expressed these encephalic regions which have relationship with stress, fear and affection, such as amygdala, hippocampus, hypothalamus and forefrontal cortex. And stress could induce changes of SP in these regions. Administration SP to central nervous system could produce behavior of fear. Stress is an important factor which induce depressive disorder. The gene damage of NK1 receptor and treated by SPA could decrease response of anxous and stress of mice. And the most obviously characteristic of SPA action is no side effects which traditional antidepressant have, such as conscious-sedation, motor neuron damage and sexual disturbance. SPA will be a new antidepressant and will be applicated in clinical. This study will to improve the key role of LHb in the development of depressive disorder, and it is LHb which mediated the antidepressive effect of SPA. To improve the LHb is the site of action of SPA in central nervous system.The result of this stuy showed:
(1)The immobile time of depressed rats which induced by chronic mild stress (CMS) were increased and the climbing time were deacreased (P<0.001). The activities of CMS rats were decreased obviously compared with that of before stress; The immobile time of depressed rats which induced by clomipramine (CLI) were longer than that of normal rats and the climbing time were shorter than that of normal rats (P<0.001). The activity of CLI rats were lower than that of normal rats. After LHb lesions, the immobile time of CMS rats and CLI rats were all decreased (P<0.05) and the climbing time were all increased (P<0.05). Inhibit LHb by lidocaine also could induce the decreased of immobile time (P<0.001) and the increased of climbing time (P<0.05) of CMS rats. The result were similar with LHb lesions.
(2)The result of radioimmunodetection showed that the level of blood cortisol of CMS rats were obviously higher than that of normal rats (P<0.01). LHb lesions could induce the decreased of blood cortisol (P<0.05).
(3)The result of immunohistochemistry showed that the expression of corticotrophic releasing hormone (CRH) were higher than that of normal rats in periventricular nucleus (PVN). The number of CRH cell were increased in PVN of CMS rats.
(4)The extracellular 5-HT level in DRN of CMS rats and CLI rats were lower than that of normal rats detected by microdialysis (P<0.05). The extracellular 5-HT level in DRN were increased after LHb lesions both in CMS rats and in CLI rats (P<0.05). The extracellular 5-HT level in DRN were not changed in sham rats (P>0.05).
(5)Local application of lidocaine into LHb induced a significant increase in the extracellular 5-HT level in DRN of CLI group (from 98.2±4.3% of baseline to 170.4±18.1% of baseline, P<0.05). Glu 1.8_g/kg significantly decreased extracellular 5-HT levels in DRN of CLI group (from 98.2±4.3% of baseline to 52.9±8.0% of baseline, P<0.001).
(6)There are no changes in FST both in CMS rats and in CLI rats after administrated of SP (0.3μg) into LHb (P>0.05). The immobile time were decreased (P<0.01) and the climbing time increased (P<0.05) after administrated SPA (0.3μg) into LHb both in CMS rats and in CLI rats. But there were no changes after adminstrated SPA/SP into LHb (P>0.05).
(7)The result of extracelluar firing showed that the firing rate of serotonergic neurons in DRN were increased after local microinjection of SPA into LHb (P<0.01). And the firing rate of serotonergic neurons in DRN were decreased after local microinjection of SP into LHb (P<0.01).
(8)SPA could decreased the firing rate of LHb neurons in slices (P<0.001), and SP could increased the firing rate of LHb neurons in slices (P<0.05).
(9)The extracellular 5-HT level in DRN were increased 28% compared with that of before administration of SPA into LHb in CMS rats (P<0.05). The extracellular 5-HT level in DRN were increased 30% compared with that of before administration of SPA into LHb in CLI rats (P<0.05). Local microinjection of SPA into LHb could induce the increasing of extracellular 5-HT in DRN both in CMS rats and in CLI rats. According to these results, we can draw the below conclusions:
(1)The depressed animal model of CMS and CLI were validity, reliability and utility. And they can be used to study depressive disorder.
(2)LHb lesions could improve the behavioral response in depressed rats via increasing the serotonin level in dorsal raphe nucleus and inhibition hypothalamic-pituitary-adrenocortical axis. From our studies, we conclude that function of the LHb is a crucial factor in the pathogenesis and therapy of depression.
(3)LHb is the site of action of SPA in central nervous system. SPA could inhibit the activity of LHb neurons. The antidepressive effect of SPA were exerted by directly inhibit LHb to increase extracellular 5-HT level in brain.
引文
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