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)

ASC (Antidepressant-Sensitive Catalepsy) mice, bred for a high predisposition to catalepsy, are characterized by depression-like behavior and decreased immune responses. Chronic administration of fluoxetine, which is a selective serotonin reuptake inhibitor antidepressant widely used in clinical practice, to mice of this strain weakened catalepsy and normalized the number of rosette-forming cells in the spleen. In mice of the parental cataleptic strain CBA/Lac, fluoxetine had no effect on the level of catalepsy or the immune response. Analysis of the effects of fluoxetine on the functional activity of 5-HT(1A) and 5-HT(2A) receptors, and the expression of 5-HT(1A) receptor genes in the frontal cortex and midbrain and 5-HT(2A) receptors in the frontal cortex, as well as the tryptophan hydroxylase-2 and the serotonin transporter genes in the midbrain showed that the antidepressant had no effect on these parameters in ASC mice, but decreased the functional activity of 5-HT(2A) receptors in CBA/Lac mice. The possibility that the actions of fluoxetine on catalepsy and the immune response in mice with depression-like states are mediated via other serotoninergic mechanisms is discussed.
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PMID:Effects of chronic fluoxetine treatment on catalepsy and the immune response in mice with a genetic predisposition to freezing reactions: the roles of types 1A and 2A serotonin receptors and the tph2 and SERT genes. 2046 12

Ca(V)2.1, which is highly expressed in the nervous system, plays an essential role in presynaptic neurotransmitter release. Although recent data suggest that the antiepileptic drug levetiracetam (LEV) inhibits presynaptic Ca(V)2.1 activity, the precise physiological role of Ca(V)2.1/LEV-regulated emotional performance has not been elucidated. We examined whether Ca(V)2.1/LEV mediates emotional behavior using a combined pharmacologic and genetic approach. Heterozygous rolling Nagoya (rol/+) mice carrying the Ca(V)2.1alpha(1) mutation demonstrated normal emotional behavior. Exposure to 75mg/kg LEV, which had no effect in wild-type controls, reduced anxiety in elevated plus maze and light-dark exploration tests and reduced depression in forced swimming and tail suspension behavioral tests in rol/+ mice. Similar behavioral patterns in motor activity were noted in wild-type and rol/+ mice injected with 0-150mg/kg LEV. The phosphorylation of tryptophan hydroxylase at serine-58 and serotonin concentration were increased in the brainstems of rol/+ mice injected with 75mg/kg LEV but not in those of wild-type controls. These results indicate that Ca(V)2.1/LEV mediates serotonin signaling leading to alterations in emotion. Our results also indicate that a combination of subthreshold pharmacologic and genetic approaches can be used to study functional signaling pathways in neuronal circuits.
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PMID:Levetiracetam-mediated emotional behavior in heterozygous rolling Nagoya Ca(V)2.1 channel mutant mice. 2057 Jun 94

The brain serotonergic system has an essential role in the physiological functions of the central nervous system and dysregulation of serotonin (5-HT) homeostasis has been implicated in many neuropsychiatric disorders. The tryptophan hydroxylase-2 (TPH2) gene is the rate-limiting enzyme in brain 5-HT synthesis, and thus is an ideal candidate gene for understanding the role of dysregulation of brain serotonergic homeostasis. Here, we characterized a common, but functional single-nucleotide polymorphism (SNP rs1386493) in the TPH2 gene, which decreases efficiency of normal RNA splicing, resulting in a truncated TPH2 protein (TPH2-TR) by alternative splicing. TPH2-TR, which lacks TPH2 enzyme activity, dominant-negatively affects full-length TPH2 function, causing reduced 5-HT production. The predicted mRNA for TPH2-TR is present in postmortem brain of rs1386493 carriers. The rs13864923 variant does not appear to be overrepresented in either global or multiplex depression cohorts. However, in combination with other gene variants linked to 5-HT homeostasis, this variant may exhibit important epistatic influences.
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PMID:A functional alternative splicing mutation in human tryptophan hydroxylase-2. 2085 48

Drugs that selectively inhibit the serotonin transporter (SERT) are widely prescribed for treatment of depression and a range of anxiety disorders. We studied the time course of changes in tryptophan hydroxylase (TPH) in four raphe nuclei after initiation of two different SERT inhibitors, citalopram and fluoxetine. In the first experiment, groups of Sprague-Dawley rats received daily meals of rice pudding either alone (n=9) or mixed with citalopram 5 mg/kg/day (n=27). Rats were sacrificed after 24 h, 7 days or 28 days of treatment. Sections of dorsal raphe nucleus (DRN), median raphe nucleus (MRN), raphe magnus nucleus (RMN) and caudal linear nucleus (CLN) were processed for TPH immunohistochemistry. Citalopram induced a significant reduction in DRN TPH-positive cell counts at 24 h (41%), 7 days (38%) and 28 days (52%). Similar reductions in TPH-positive cell counts were also observed at each timepoint in the MRN and in the RMN. In the MRN, citalopram resulted in significant reductions at 24 h (26%), 7 days (16%) and 28 days (23%). In the RMN, citalopram induced significant reductions of TPH-positive cell counts at 24 h (45%), 7 days (34%) and 28 days (43%). By contrast, no significant differences between control and treatment groups were observed in the CLN at any of the time points that we studied. To investigate whether these changes would occur with other SERT inhibitors, we conducted a second experiment, this time with a 28-day course of fluoxetine. As was observed with citalopram, fluoxetine induced significant reductions of TPH cell counts in the DRN (39%), MRN (38%) and RMN (41%), with no significant differences in the CLN. These results indicate that SERT inhibition can alter the regulation of TPH, the rate limiting enzyme for serotonin biosynthesis. This persistent and regionally specific downregulation of serotonin biosynthesis may account for some of the clinical withdrawal symptoms associated with drugs that inhibit SERT.
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PMID:Role of serotonin transporter inhibition in the regulation of tryptophan hydroxylase in brainstem raphe nuclei: time course and regional specificity. 2086 30

Based on genetic variation, there is accumulating evidence that altered function of tryptophan hydroxylase-2 (TPH2), the enzyme critical for synthesis of serotonin (5-HT) in the brain, plays a role in anxiety-, aggression- and depression-related personality traits and in the pathogenesis of disorders featuring deficits in cognitive control and emotion regulation. Here, we appraise the genetic and neurobiological evidence to illustrate the critical role of TPH2 in central 5-HT system function and in the pathophysiology of a wide spectrum of disorders of cognitive control and emotion regulation, ranging from depression to attention-deficit/hyperactivity disorder (ADHD), a phenotype commonly associated with difficulties in the control of emotion and with a high co-morbidity of depression. Findings from psychophysiological and functional imaging studies are indicative of various TPH2 polymorphisms directly influencing serotonergic function and thus impacting on mood disorders and on the response to antidepressant treatment. Especially a combination with uncontrollable stress seems to potentiate these effects linking gene-environment interaction directly with behavioral dysfunction in human and animal models. TPH2-deficient mice display alterations in anxiety-like behavior which is accompanied by adaptational changes of 5-HT(1A) receptors and its associated signaling pathway. Mouse models in conjunction with cognitive neuroscience approaches in humans are providing unexpected results and it may well be that future research on TPH2 will provide an entirely new view of 5-HT in brain development and function related to neuropsychiatric disorders.
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PMID:Tryptophan hydroxylase-2 (TPH2) in disorders of cognitive control and emotion regulation: a perspective. 2125 71

Most pregnant women are at risk of showing some emotional abnormality, since some biological functions such as hormonal systems may dramatically change in pregnancy. Some of them may be exposed to strong stress as hesitation of positive drug therapies because of worries regarding adverse effects on the embryo. A growing body of evidence suggests that prenatal stress increases the vulnerability to neuropsychiatric disorders, including depression and anxiety. However, the mechanisms involved are still unknown. To clarify the influence of exposure to prenatal stress on emotional development, we examined behavioral responses in offspring exposed to weak- or strong-prenatal restraint stress. We found that offspring that had been exposed to strong stress displayed anxiety-like behavior as determined by the elevated plus-maze test. It has been widely accepted that central serotonin (5-hydroxytryptamine; 5-HT) neurons play a critical role in emotional behaviors. Immunohistochemical studies showed that exposure to strong-prenatal restraint stress increased the expression of 5-HT-positive cells in the dorsal raphe nuclei in mice. Moreover, under these conditions, tryptophan hydroxylase-like immunoreactivities were also dramatically increased. In contrast, these behavioral and neurochemical abnormalities were not observed in offspring that had been exposed to weak-prenatal restraint stress. These findings indicate that exposure to excessive prenatal stress induces anxiety-like behavior together with disruption of the development of 5-HT neurons in mice.
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PMID:Prenatal stress induces anxiety-like behavior together with the disruption of central serotonin neurons in mice. 2132 May 53

Early adverse experiences resulting from maternal separation may lead to neuronal cell death and they can eventually cause memory impairment. In this study, we investigated the effects of postnatal treadmill exercise on the long-term memory capability, spatial learning ability, and depressive state, on the 5-hydroxytryptamine (5-HT, serotonin) synthesis and tryptophan hydroxylase (TPH) expression in the dorsal raphe nuclei, and on the apoptosis and cell proliferation in the hippocampal dentate gyrus of rat pups following maternal separation. The rat pups in the maternal separation groups were separated from their respective mothers on the postnatal day 14. The rat pups in the maternal separation group showed depressive state with deceased memory capability and learning ability compared to the rat pups in the maternal care group. Postnatal treadmill exercise increased memory capability and learning ability and alleviated depressive state of the rat pups in the maternal separation group. The 5-HT synthesis and TPH expression in the dorsal raphe nuclei and cell proliferation in the hippocampal dentate gyrus were significantly decreased in the maternal-separated rat pups, and postnatal treadmill exercise increased 5-HT synthesis, the TPH expression, and the cell proliferation. In contrast, apoptotic neuronal cell death in the hippocampal dentate gyrus was significantly increased in the maternal-separated rat pups, and postnatal treadmill exercise suppressed the maternal separation-induced apoptosis. The present results demonstrated that postnatal treadmill exercise alleviated maternal separation-induced depression with decrease of memory capability and learning ability, by suppressing apoptotic neuronal cell death and by enhancing cell proliferation.
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PMID:Effects of postnatal treadmill exercise on apoptotic neuronal cell death and cell proliferation of maternal-separated rat pups. 2135 11

It has been suggested that serotonergic hypofunction and serotonergic pathway genes underlie the somatic symptoms of somatoform disorders. We examined a variety of serotonin-related gene polymorphisms to determine whether undifferentiated somatoform disorder is associated with specific serotonin-related gene pathways. Serotonin-related polymorphic markers were assessed using single nucleotide polymorphism (SNP) genotyping. One hundred and two patients with undifferentiated somatoform disorder and 133 healthy subjects were enrolled. The genotype and allele frequencies of tryptophan hydroxylase (TPH)1 A218C, TPH2 rs1386494, serotonin receptor 2A-T102C (5-HTR 2A-T102C), 5-HTR 2A-G1438A and serotonin transporter (5HTTLPR) gene were compared between the groups. The Hamilton Rating Scale for Depression and the somatization subscale of the Symptom Checklist-90-Revised (SCL-90-R) were used for psychological assessment. Patients with undifferentiated somatoform disorder had higher frequencies of the TPH1 C allele than healthy controls (p=0.02) but the difference was not significant after Bonferroni correction. The frequency of TPH1 genotype also did not differ significantly between the patients and the healthy controls, nor did TPH2 rs1386494, 5-HTR 2A-T102C, 5-HTR 2A-G1438A or 5HTTLPR allele and genotype frequencies differ significantly between the two groups. These findings suggest that a variety of serotonin-related gene pathways are unlikely to be definite genetic risk factors for undifferentiated somatoform disorder. Therefore, the pathogenesis of the disorder may be related to epigenetic factors, including psychosocial and cultural factors. Nonetheless, future studies need to include a larger sample of subjects and polymorphisms of more serotonin-related gene variants.
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PMID:Serotonin-related gene pathways associated with undifferentiated somatoform disorder. 2153 67

Mechanisms underlying stress-induced depression and antidepressant drug action were shown to involve alterations in serotonergic (5-HT) neurotransmission and expression of genes coding for proteins associated with neurotrophic signaling pathways and cell-survival in the hippocampus and cortex. Expression of these genes in the brainstem containing 5-HT neurons may also be related to vulnerability or resilience to stress-related psychopathology. Here we investigated 5-HT markers and expression of genes for Brain-Derived Neurotrophic Factor (BDNF) and apoptotic proteins in the brainstem in relation to swim stress-induced behavioral despair. We found that anti-apoptotic Bcl-xL gene is sensitive to stress during the course of fluoxetine administration. Responsiveness of this gene to stress appeared concomitantly with an antidepressant-like effect of fluoxetine in the forced swim test. Bcl-xL transcript levels showed negative correlations with duration of immobility in the test and 5-HT turnover in the brainstem. In contrast, BDNF and pro-apoptotic protein Bax mRNA levels were unchanged by either fluoxetine or stress, suggesting specificity of Bcl-xL gene responses to these treatments. We also found that the levels of mRNAs for tryptophan hydroxylase-2 (TPH2) and 5-HT transporter (5-HTT) were significantly down-regulated following prolonged treatment with fluoxetine, but were not affected by stress. Unlike TPH2 and 5-HTT, 5-HT1A receptor mRNA levels were not altered by fluoxetine but significantly increased in response to swim stress. These data show that long-term fluoxetine treatment leads to changes in 5-HT and Bcl-xL responses to stress associated with antidepressant-like effects of the drug. This article is part of a Special Issue entitled 'Anxiety and Depression'.
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PMID:Stress-induced activation of the brainstem Bcl-xL gene expression in rats treated with fluoxetine: correlations with serotonin metabolism and depressive-like behavior. 2174 Sep 20

We have previously reported that inhibition of the serotonin transporter (SERT) by selective serotonin reuptake inhibitor (SSRI) fluoxetine significantly reduces the number of tryptophan hydroxylase (TPH)-positive cells in the dorsal raphe nucleus (DRN). We have been interested in exploring whether this SSRI-induced change in TPH might be modified by housing in an enriched environment. Like SSRI antidepressants, environmental enrichment (EE) and physical exercise have been found to have efficacy in the prevention and alleviation of depression. We postulated that EE with exercise and SERT inhibition would similarly affect TPH regulation and that EE with exercise might modify the effect of fluoxetine on TPH. Three week old male Sprague-Dawley rats were housed in either a standard cage (SE) or an enriched environment (EE). SE animals were singly housed with no access to enrichment objects. EE animals were group housed and were provided with various enrichment objects (e.g. running wheel) that were changed and rearranged regularly. Nine weeks after the experiment began, the rats were randomly assigned to one of four treatment groups: (1) SE control; (2) SE fluoxetine; (3) EE control; or (4) EE fluoxetine. Fluoxetine (5 mg/kg/day) was placed in the drinking water. Sections of DRN were processed for TPH immunohistochemistry. The number of TPH-positive cells was determined by blinded, manual counting. Results were analyzed by analysis of variance (ANOVA) followed by post-hoc Tukey tests. Significance was set at P < 0.05. For animals housed in a standard environment, fluoxetine induced a significant 29% reduction in the number of TPH-immunoreactive cells in the DRN. A similar reduction in TPH immunoreactivity was observed in animals that were housed in an enriched environment but not exposed to fluoxetine (39%). The number of TPH-positive cells in the DRN for animals housed in an enriched environment and exposed to fluoxetine was not significantly different than animals housed in an enriched environment and not exposed to fluoxetine. The reduction of TPH immunoreactivity in the DRN by EE with exercise suggests that a modified housing environment and voluntary exercise affects regulation of TPH, possibly via a mechanism similar to that of SERT inhibitors. This downregulation of serotonin biosynthesis by fluoxetine and EE with exercise may ultimately play a role in the therapeutic action of both interventions.
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PMID:The comparative effects of environmental enrichment with exercise and serotonin transporter blockade on serotonergic neurons in the dorsal raphe nucleus. 2212 Oct 41


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