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)

Modulatory actions of a metabotropic 5-HT1A&7 membrane receptor agonist and antagonist [(+/-)-8-hydroxy-2-(di-n-propylamino)-tetralin; N-[2-[4-(2-methoxyphenyl)-1-piperazinyl]ethyl]-N-(2-pyridinyl) cyclohexane-carboxamide] and an ionotropic 5-HT3 membrane receptor agonist and antagonist [2-methyl-serotonin (2-Me 5-HT); N-(1-azabicyclo[2.2.2]oct-3-yl)-6-chloro-4-methyl-3-oxo-3,4-dihydro-2H-1,4-benzoxazine-8-carboxamide hydrochloride] were investigated on dorsal horn interneurons mediating reflex actions of group II muscle afferents. All drugs were applied ionophoretically in deeply anesthetized cats. Effects of agonists were tested on extracellularly recorded responses of individual interneurons evoked by electrical stimulation of group II afferents in a muscle nerve. Effects of antagonists were tested against the depression of these responses after stimulation of raphe nuclei. The results show that both 5-HT1A&7 and 5-HT3 membrane receptors are involved in counteracting the activation of dorsal horn interneurons by group II afferents. Because only quantitative differences were found within the sample of the tested neurons, these results suggest that modulatory actions of 5-HT on excitatory and inhibitory interneurons might be similar. The relationship between 5-HT axons and axons immunoreactive for the 5-HT3A receptor subunit, which contact dorsal horn interneurons, was analyzed using immunofluorescence and confocal microscopy. Contacts from both types of axons were found on all interneurons, but their distribution and density varied, and there was no obvious relationship between them. In two of six interneurons, 5-HT3A-immunoreactive axons formed ring-like arrangements around the cell bodies. In previous studies, axons possessing 5-HT3 receptors were found to be excitatory, and as 2-Me 5-HT depressed transmission to dorsal horn interneurons, the results indicate that 5-HT operates at 5-HT3 receptors presynaptic to these neurons to depress excitatory transmission.
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PMID:Membrane receptors involved in modulation of responses of spinal dorsal horn interneurons evoked by feline group II muscle afferents. 1565 94

5-Hydroxytryptamine (5-HT) transmission has been implicated in memory and in depression. Both 5-HT depletion and specific 5-HT agonists lower memory performance, while depression is also associated with memory deficits. The precise neuropharmacology and neural mechanisms underlying these effects are unknown. We used neural network simulations to elucidate the neuropharmacology and network mechanisms underlying 5-HT effects on memory. The model predicts that these effects are largely dependent on transmission over the 5-HT1A and 5-HT3 receptors, which regulate the selectivity of retrieval. It also predicts differential memory deficit profiles for 5-HT depletion and overactivation. The latter predictions were confirmed in studies with healthy and depressed participants undergoing acute tryptophan depletion or ipsipirone challenge. The results suggest that the memory impairments in depressed subjects may be related to 5-HT undertransmission, and support the notion that 5-HT1A agonists ameliorate memory deficits in depression.
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PMID:Effects of 5-HT on memory and the hippocampus: model and data. 1613 65

Substance P (SP)/Neurokinin 1 (NK1) receptor pathways have been repeatedly implicated in the pathophysiology of central, pulmonary, and gastric disorders. A large body of evidence that has been generated from animal experiments indicates that treatment with selective NK1 receptor antagonists might be effective in the treatment of certain forms of disorders, analgesia, depression, migraine, asthma, or gastrointestinal disorders. Accordingly, numerous NK1 receptor antagonists have either been synthesized and are under clinical development, or have already been tested in clinical trials. However, the initial encouraging clinical results were followed by repeated demonstration of a lack of effectiveness. Up to now, only one NK1 receptor antagonist, aprepitant, is available for therapeutical use. Aprepitant is a selective high-affinity human SP/NK1 receptor antagonist approved by the FDA in 2003. Aprepitant is indicated for prophylaxis of acute- and delayed-phase nausea and emesis caused by chemotherapy regimens. It is used in combination with a 5-hydroxytryptamine (5-HT3) antagonist and a corticosteroid. It is the first antiemetic agent that acts by binding the NK1 receptor. Research continues and novel molecules may show better pharmacokinetic and pharmacodynamic properties and, therefore, may achieve therapeutic success.
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PMID:[Neurokinin 1 receptor antagonists--between hope and disappointment]. 1679 96

There is an association between depression and chronic pain, and some antidepressants exert antinociceptive effects in humans and laboratory animals. We examined the effects of fluvoxamine, a selective serotonin reuptake inhibitor, on mechanical allodynia and its mechanism of action in the mouse chronic pain model, which was prepared by partially ligating the sciatic nerve. The antiallodynic effect was measured using the von Frey test. Fluvoxamine produced antiallodynic effects following both systemic and intrathecal administration. In 5-hydroxytryptamine (5-HT)-depleted mice, prepared by intracerebroventricular injection of 5,7-dihyroxytryptamine, the fluvoxamine-induced antiallodynic effect was significantly attenuated. The antiallodynic effects of systemic fluvoxamine were also reduced by both systemic and intrathecal administration of ketanserin, a 5-HT2A/2C receptor antagonist. In addition, fluvoxamine also induced antinociceptive effect in the acute paw pressure test, and this effect was antagonized by the 5-HT3 receptor antagonist granisetron. These results indicate that fluvoxamine exerts its antiallodynic effects on neuropathic pain via descending 5-HT fibers and spinal 5-HT2A or 5-HT2C receptors, and the antinociception on acute mechanical pain via 5-HT3 receptors.
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PMID:Fluvoxamine, a selective serotonin reuptake inhibitor, exerts its antiallodynic effects on neuropathic pain in mice via 5-HT2A/2C receptors. 1684 19

Recent hypotheses suggest that changes in neuronal structure and connectivity may underlie the etiology of depression. The medial prefrontal cortex (mPFC) is affected by depression and shows neuronal remodeling during adulthood. This plasticity may be mediated by the polysialylated form of the neural cell adhesion molecule (PSA-NCAM), which is intensely expressed in the adult mPFC. As the expression of PSA-NCAM is increased by serotonin in other cerebral regions, antidepressants acting on serotonin reuptake may influence PSA-NCAM expression and thus counteract the effects of depression by modulating neuronal structural plasticity. Using immunohistochemistry, we have studied the relationship between serotoninergic fibers and PSA-NCAM expressing neurons in the adult rat mPFC and the expression of serotonin receptors in these cells. The effects of fluoxetine treatment for 14 days on mPFC PSA-NCAM expression have also been analyzed. Although serotoninergic fibers usually do not contact PSA-NCAM immunoreactive neurons, most of these cells express 5-HT3 receptors. In general, chronic fluoxetine treatment induces significant increases in the number of PSA-NCAM immunoreactive neurons and in neuropil immunostaining and coadministration of the 5-HT3 antagonist ondansetron blocks the effects of fluoxetine on PSA-NCAM expression. These results indicate that fluoxetine, acting through 5-HT3 receptors, can modulate PSA-NCAM expression in the mPFC. This modulation may mediate the structural plasticity of this cortical region and opens new perspectives on the study of the molecular bases of depression.
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PMID:Chronic fluoxetine treatment increases the expression of PSA-NCAM in the medial prefrontal cortex. 1690 Jan 4

The neurotransmitter dopamine (DA) has a long association with normal functions such as motor control, cognition, and reward, as well as a number of syndromes including drug abuse, schizophrenia, and Parkinson's disease. Studies show that serotonin (5-HT) acts through several 5-HT receptors in the brain to modulate DA neurons in all 3 major dopaminergic pathways. There are at least fourteen 5-HT receptor subtypes, many of which have been shown to play some role in mediating 5-HT/DA interactions. Several subtypes, including the 5-HT1A, 5-HT1B, 5-HT2A, 5-HT3 and 5-HT4 receptors, act to facilitate DA release, while the 5-HT2C receptor mediates an inhibitory effect of 5-HT on DA release. Most 5-HT receptor subtypes only modulate DA release when 5-HT and/or DA neurons are stimulated, but the 5-HT2C receptor, characterized by high levels of constitutive activity, inhibits tonic as well as evoked DA release. This review summarizes the anatomical evidence for the presence of each 5-HT receptor subtype in dopaminergic regions of the brain and the neuropharmacological evidence demonstrating regulation of each DA pathway. The relevance of 5-HT receptor modulation of DA systems to the development of therapeutics used to treat schizophrenia, depression, and drug abuse is discussed. Lastly, areas are highlighted in which future research would be maximally beneficial to the treatment of these disorders.
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PMID:Pharmacologic mechanisms of serotonergic regulation of dopamine neurotransmission. 1704 11

As has been shown by a number of working groups, primary fibromyalgia syndrome does not represent a single clinical entity. It is possible to distinguish between a subgroup with high pain sensitivity and no associated psychiatric condition, a second subgroup characterized by depression and concomitant pain symptoms associated with fibromyalgia syndrome, and a third group with somatoform pain disorder of the fibromyalgia type. Bland inflammatory processes must be considered as the cause in the first group, while depression is the underlying reason for the development of pain in the second group. In the third group, serious previous or still existing psychological problems or also insufficient coping with illness symptoms must be regarded as the reason for pain chronification. Group 1 benefits from a blocking of the 5-HT3 receptors by means of tropisetron, for example. This not only affects pain chronification but also the inflammatory process itself. Group 2 needs antidepressant treatment, whereas the focus should be on psychotherapy is group 3. Groups 1 and 2 will also profit from multimodal physical treatment programs; to a certain extent this applies to group 3 as well. So-called mixed types require a combination of therapeutic measures.
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PMID:[Subgroups of fibromyalgia]. 1739 87

As has been shown by a number of working groups, primary fibromyalgia syndrome does not represent a single clinical entity. It is possible to distinguish between a subgroup with high pain sensitivity and no associated psychiatric condition, a second and a third subgroup characterized by depression associated with fibromyalgia syndrome, and a fourth group with somatoform pain disorder of the fibromyalgia type. Mild inflammatory processes must be considered as the cause in the first group, while depression is combined with fibromyalgia in the second and the third group. In the fourth group, serious previous or still existing psychological problems or also insufficient coping with illness symptoms must be regarded as the reason for pain chronification. Group 1 benefits from a blocking of the 5-HT3 receptors by means of tropisetron, for example. This does not only affect pain chronification but also the inflammatory process itself. Group 2 and 3 needs antidepressant treatment, whereas the focus should be on psychotherapy in group 4. Groups 1, 2 and 3 will also profit from multimodal physical treatment programs, to a certain extent this applies to group 4 as well. So-called mixed types require a combination of therapeutic measures.
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PMID:The classification of fibromyalgia syndrome. 1765 20

The development of therapeutic strategies for cognitive dysfunction remains one of the primary goals in the treatment of schizophrenia. The pharmacodynamic profile of mirtazapine, an antidepressant that enhances noradrenergic and serotonergic transmission, is based on a presynaptic alpha2 antagonism and postsynaptic 5-HT2 and 5-HT3 antagonism. Mirtazapine shares some pharmacological similarities with that of clozapine. This 8-week open label trial aimed to discover whether the addition of 30 mg mirtazapine could potentiate the effects on cognition of an ongoing stabilized clozapine therapy in 15 persons who met the criteria for chronic schizophrenia in the Diagnostic and Statistical Manual of Mental Disorders (4th ed., text rev.; American Psychiatric Association, 2000). Mirtazapine adjunction was well tolerated and induced a significant improvement in cognitive performance, as measured by the Repeatable Battery for the Assessment of Neuropsychological Status (RBANS; Randolph, 1998) total score and by the subscales for immediate and delayed memory (p<.01). Since Hamilton Depression Rating Scale (HAM-D; Hamilton, 1967), Brief Psychiatric Rating Scale (BPRS; Overall & Gorham, 1962), and Scale for the Assessment of Negative Symptoms (SANS; Andreasen, 1989) scores at Week 8 did not show significant differences from baseline, the improvements in the effects of clozapine on cognition observed after the addition of mirtazapine seemed to be a direct rather than an indirect action of this drug (e.g., via mood or other psychopathological symptoms). These findings suggest a potential role for mirtazapine as a useful strategy to augment the efficacy of clozapine in the treatment of cognitive dysfunctions in chronic schizophrenia.
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PMID:Add-on mirtazapine enhances effects on cognition in schizophrenic patients under stabilized treatment with clozapine. 1817 9

The 5-hydroxytryptamine-3 (5-HT3) receptor mediates the fast excitatory neurotransmission of serotonin and is known to mediate the nausea/emesis induced by radio/chemotherapy and anesthetics. A polymorphism encoding the variation Y129S in the 5-HT3B subunit exists in high frequency in the general population and has been shown to be inversely correlated to the incidence of major depression in women. We show that 5-HT3AB(Y129S) receptors exhibit a substantially increased maximal response to serotonin compared with WT receptors in two fluorescence-based cellular assays. In electrophysiological recordings, the deactivation and desensitization kinetics of the 5-HT3AB(Y129S) receptor are 20- and 10-fold slower, respectively, than those of the WT receptor. Single-channel measurements reveal a 7-fold-increased mean open time of 5-HT3AB(Y129S) receptors compared with WT receptors. The augmented signaling displayed by 5-HT3AB(Y129S) receptors may confer protection against the development of depression. The variant also may influence the development and/or treatment of nausea and other disorders involving 5-HT3 receptors. Thus, the impact of the high-frequency variant 5-HT3B(Y129S) on 5-HT3AB receptor signaling calls for a search for additional phenotypes, and the variant may thus aid in establishing the role of the 5-HT3AB receptor in pathophysiology.
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PMID:High-frequency HTR3B variant associated with major depression dramatically augments the signaling of the human 5-HT3AB receptor. 1818 10


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