Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0011570 (depression)
 172,036 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Dopamine neurons in the ventral tegmental area (VTA) play a very important role in a variety of physiological as well as addictive behaviors. However, a clear understanding of the cellular mechanisms underlying these behaviors is still missing. Within the VTA, recent studies have shown that forms of synaptic plasticity such as long-term potentiation (LTP) and long-term depression (LTD) are produced by drugs of abuse. The main goal of this review is to discuss the relationship between plasticity at excitatory synapses in the VTA and addiction-associated behaviors such as behavioral sensitization and cocaine self-administration. Furthermore, recent studies have highlighted the role of orexin/hypocretin and corticotropin-releasing factor (CRF) as powerful modulators of excitatory synaptic transmission in the VTA. Here, we will discuss the potential correlation between the ability of these peptides in mediating excitatory synaptic transmission and the development of stress- and drug-dependent behaviors. Taken together, the results from the studies reviewed here shed new light on the mechanistic role of plasticity at glutamatergic synapses in the VTA in mediating addictive, as well as stress-dependent behaviors.
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PMID:Role of orexin/hypocretin and CRF in the formation of drug-dependent synaptic plasticity in the mesolimbic system. 1869 70

Depression is associated with a deficiency of serotonergic neurons that have been found to suppress orexinergic neurons, which in turn activate these neurons in a feedback loop. This evidence suggests that orexins may be involved in the pathology of depression. Long Evans rats were treated with clomipramine (CLI) and saline (SAL) from postnatal days 8 through 21. One set of rats from both groups was sacrificed at 35 days of age for quantification of orexins in multiple brain regions. At 3-4 months of age a second set of rats was tested for immobility in a forced swim procedure, a common test for depressive signs in rats, and a third set was sacrificed for the quantification of orexins. Compared with the control rats, adult rats with neonatal CLI treatment had (1) increased forced swim immobility and (2) increased orexins A and B in the hypothalamus. However, both orexins A and B levels were decreased in multiple brain regions in the juvenile CLI rats compared with same-age controls. We concluded that although orexin levels were decreased in juvenile CLI rats, adult CLI rats with features of depression had significantly higher levels of hypothalamic orexins compared with adult controls. These results imply that orexins are likely to be involved in the pathological regulation of depression.
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PMID:Changes in brain orexin levels in a rat model of depression induced by neonatal administration of clomipramine. 1875 73

Orexins are neuropeptides that are localized in neurons within the lateral hypothalamus and regulate feeding behavior. The lateral hypothalamus plays an important role in not only feeding but also in the central regulation of gut function. Along this line, accumulating evidence has shown that orexins act in the central nervous system to regulate gastrointestinal functions. The purpose of this review is to summarize recent relevant findings on brain orexins and the digestive system, and discuss the pathophysiological roles of these peptides. Centrally administered orexin or endogenously released orexin in the brain potently stimulates gastric acid secretion in rats. The vagal cholinergic pathway is involved in the orexin-induced stimulation of acid secretion. Because of its stimulatory action on feeding, it can be hypothesized that orexin in the brain is a candidate mediator of cephalic phase gastric secretion. In addition, brain orexin may be involved in the development of depression and functional gastrointestinal disorders, which are frequently accompanied by inhibition of gut function, because lack of orexin activity might cause the inhibition of gastric physiological processes and evoke a depressive state. These lines of evidence suggest that orexin in the brain is a potential molecular target for treatment of functional gastrointestinal disorders.
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PMID:Role of orexin in central regulation of gastrointestinal functions. 1880 26

A decrease in orexin-A (OX-A) levels has been reported to be associated with depression. It is also well known that stress and depression can disrupt neurogenesis in the dentate gyrus of the hippocampus; however, it is unclear how OX-A is involved in depression and/or neurogenesis. In the present study, we investigated the effect of i.c.v. administration of OX-A on the forced swimming test (FST), an accepted behavioral screen of antidepressant-like activity, and on the cell proliferation with bromodeoxyuridine (BrdU) in the dentate gyrus at 4 days after i.c.v. administration of OX-A. OX-A administration (140 pmol/mouse) led to a significant reduction in animal immobility in the FST, without affecting spontaneous locomotor activities or serum corticosterone levels. In addition, the number of BrdU-positive cells in the dentate gyrus was significantly increased in OX-A-treated mice in vivo; however, OX-A did not affect the percentage of doublecortin-positive cells in the dentate gyrus. The proliferation of neural progenitor cells derived from rat fetal brain was not affected by OX-A treatment in vitro, and the orexin receptor 1 (OXR1) protein was not expressed in these cells. Treatment with the OXR1 antagonist SB-334867 (30 mg/kg, i.p.) blocked both the OX-A-induced decrease in the immobility of FST and increase in BrdU-positive. Moreover, the OX-A-induced increase in neuropeptide Y (NPY)-positive cells in the hilus of the dentate gyrus was blocked by SB-334867. These results suggest that OX-A induces an antidepressive-like effect, at least in part, via the enhancement of cell proliferation in the dentate gyrus. These effects of OX-A also may be partly relevant to the regulation of the NPY system in the hilus of the dentate gyrus.
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PMID:I.c.v. administration of orexin-A induces an antidepressive-like effect through hippocampal cell proliferation. 1895 52

Migraine is an episodic and popular headache disorder. Migraine arises from a primary cerebral dysfunction that leads to activation of trigeminovascualr system. In the 1940s cerebral arterial constriction and the following enhanced dilatation was considered to induce migraine attack. Next, the cortical neuronal change that is well linked to the migraine aura was considered to be primary mechanism of migraine attack. Recently, the trigeminovascular system has a main role in the pathophysiological mechanism of the migraine. From the animal studies, cortical spreading depression (CSD) may induce the activation of the trigeminovascular system and may be a trigger of the migraine pathological mechanism. Also the activation or the functional change of brainstem nuclei, involving periaqueductal grey matter, raphe nuclei, and locus ceruleus, may be a trigger of the migraine attack. We have showed that the level of plasma orexin-A in the migraine patients during headache free period is lower than that of control. From the animal experiments, we also showed that intracerebroventricular injection of orexin induces the increase in the cerebral cortical blood flow, and that the intraarterial application of orexin cannot increase the cerebral blood flow. We consider that orexinegic neurons in the lateral hypothalamus may be a generator of migraine.
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PMID:[Pathophysiology of migraine--migraine generator]. 1919

We have studied the effects of orexin-A on NMDA component of registered field potentials in pyramidal (str. pyramidale) and radial layers (st. radiatum) of CA-1 field of the hippocampus. To facilitate generation of NMDA responses in vitro experiments were performed in Mg(2+)- free solution. From field excitatory postsynaptic potential (EPSP), which was induced by stimulation of Schaffer collaterals, NMDA component was isolated using modified physiological solution: bicuculline metiodide (20-40 microM) and CNQX (5 microM) were eddied for removing GABA-ergic inhibition and blocking AMPA-glutamatergic receptor-mediated responses, respectively. Application of orexin-A (100 nM, for 5 -15 min) evoked inhibition of NMDA component of population spike (84.4+/-5%, n=7) and long-term depression of isolated NMDA component of field EPSP, which was made up (77.7+/-2.8%, n=12) comparing with control after 45 min of orexin-A application. Orexin-A mediated depression starts after 7-10 min of application, which is sufficient for NE release from adrenergic terminals in the hippocampus. As the agonist of alpha-adrenoreceptors clonidine completely mimicked the effects of orexin-A possible involvement of adrenergic system of the brain in these effects are considered.
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PMID:Orexin-A induces long-term depression of nmda responses in CA-1 field of hippocampal slices. 1943 48

The hypocretin (orexin) neurons in the lateral hypothalamus play a crucial role in the promotion of arousal. Adenosine, an endogenous sleep-promoting factor, modulates both neuronal excitatory and synaptic transmission in the CNS. In this study, the involvement of endogenous adenosine in the regulation of excitatory glutamatergic synaptic transmission to hypocretin neurons was investigated in the hypothalamic slices from transgenic mice by using different frequencies of stimulation. A train of low-frequency stimulation (0.033, 1 Hz) had no effect on the amplitude of evoked excitatory postsynaptic currents (evEPSCs) in hypocretin neurons. Blockade of adenosine A1 receptors with selective A1 receptor antagonist 8-cyclopentyltheophylline (CPT), the amplitude of evEPSCs did not change during 0.033 and 1 Hz stimuli. When the frequency of stimulation was increased upto 2 Hz, a time-dependent depression of amplitude was recorded in hypocretin neurons. Administration of CPT caused no significant change in depressed synaptic response induced by 2 Hz stimulus. While depression induced by 10 and 100 Hz stimuli was partially inhibited by the CPT but not by the selective A2 receptor antagonist 3,7-dimethyl-1-(2-propynyl)xanthine. Further findings have demonstrated that high-frequency stimulation could induce long-term potentiation (LTP) of glutamatergic synaptic transmission to hypocretin neurons in acute hypothalamic slices. The experiments with CPT suggested that A1 receptor antagonist could facilitate the induction of LTP, indicating that endogenous adenosine, acting through A1 receptors, may suppress the induction of LTP of excitatory synaptic transmission to hypocretin neurons. These results suggest that in the hypothalamus, endogenous adenosine will be released into extracellular space in an activity-dependent manner inhibiting both basal excitatory synaptic transmission and LTP in hypocretin neurons via A1 receptors. Our data provide further support for the notion that hypocretin neurons in the lateral hypothalamus may be another important target involved in the endogenous adenosine modulating the sleep and wakefulness cycle in the mammalian CNS.
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PMID:Activity-dependent release of adenosine inhibits the glutamatergic synaptic transmission and plasticity in the hypothalamic hypocretin/orexin neurons. 1946 88

The mechanism of dead-in-bed syndrome (DBS), a rare but devastating condition that mainly affects young type 1 diabetes patients, remains mysterious. A new theory is proposed to explain this syndrome. This theory suggests that repeated episodes of hypoglycaemia-induced adaptation in orexin-A neurons cause (i) defective awakening and (ii) hypotonia of upper airway muscles during sleep. Consequently, due to the combined effect of these factors, long-term exposure of intermittent hypoxia occurs, leading to a combination of factors - such as depression of ventilation, increase in sympathetic tone, fluctuations in intrathoracic pressure and cardiac arrhythmias - these in conjunction with an underlying cardiovascular pathology (genetically inherited or acquired) cause cardio-respiratory failure and thus sudden death during sleep. This mechanism can be generalized to explain other cases of sudden unexplained nocturnal deaths including sudden infant deaths (SIDs).
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PMID:The mechanism of dead-in-bed syndrome and other sudden unexplained nocturnal deaths. 1960 34

A voluminous literature describes the relationship between disturbed sleep and depression. The breakdown of sleep is one of the cardinal features of depression and often also heralds its onset. Frequent arousals, periods of wakefulness and a short sleep onset REM latency are typical polysomnographic features of depression. The short latency to REM sleep has been attributed to the combination of a monoaminergic deficiency and cholinergic supersensitivity and these irregularities have been proposed to form the biological basis of the disorder. A similar imbalance between monoaminergic and cholinergic neurotransmission has been found in narcolepsy, a condition in which frequent awakenings, periods of wakefulness and short sleep onset REM latencies are also characteristic findings during sleep. In many cases of narcolepsy, this imbalance appears to result from a deficiency of hypocretin but once established, whether in depression or narcolepsy, this disequilibrium sets the stage for the dissociation or premature appearance of REM sleep and for the dissociation of the motor inhibitory component of REM sleep or cataplexy. In the presence of this monoaminergic/cholinergic imbalance, gammahydroxybutyrate (GHB) may acutely further reduce the latency of REM sleep and induce cataplexy, in both patients with narcolepsy or depression. On the other hand, the repeated nocturnal application of GHB in patients with narcolepsy improves the continuity of sleep, prolongs the latency to REM sleep and prevents cataplexy. Evidence to date suggests that GHB may restore the normal balance between monoaminergic and cholinergic neurotransmission. As such, the repeated use of GHB at night and the stabilization of sleep over time makes GHB an effective treatment for narcolepsy and a potentially effective treatment for depression.
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PMID:Narcolepsy and depression and the neurobiology of gammahydroxybutyrate. 1965 34

It was discovered in 2000 that a deficit of hypocretin/orexin neurons is responsible for causing narcolepsy. Today, agonists for orexin receptors are being explored in order to establish an orexin replacement therapy, but the process is still at the stage of research. On the other hand, orexin antagonists are now undergoing clinical trials as a hypnotic. Activation of the dopamine system is effective against hypersomnia, and activation of the noradrenaline system is effective against cataplexy. Therefore, these two types of drugs have been used for treatment. Methylphenidate was mainly used, but recently modafinil has become mainstream. The action mechanism of methylphenidate is reuptake inhibition and release stimulation of dopamine. The action mechanism of modafinil is not fully explained, but is thought to be reuptake inhibition of dopamine. When methylphenidate was used for disorders other than narcolepsy, such as depression, dependence on the drug and abuse became an issue, and methylphenidate is no longer available for depression. It has been said that narcoleptic patients have a tendency to control the doses of methylphenidate at a low level of their own accord, and that they have a significantly low risk of developing a dependency on the drug. It has also been observed in mice with orexin deficit produced by molecular genetics that they have a significantly low development of dependency on amphetamine, a relative compound of methylphenidate. On the other hand, modafinil has been found to cause very little dependence, and is chosen as the principal drug in treatment. It was recently discovered that the histamine neurons, which are downstream of orexin neurons, are responsible for controlling arousal. It was also discovered that the CSF histamine was low in narcolepsy and other hypersomnia of central origin. Histamine H3 antagonists are being explored as a treatment for hypersomnia. H3 receptors are auto receptors located in the brain histamine neuron, and agonists act for suppression, antagonists for activation. They have shown good results in the animal experiments and phase 2 of clinical experiments.
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PMID:[Recent advance of treatments for narcolepsy and hypersomnia]. 1966 60


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