Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P08908 (5-HT1A)
 5,574 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The level of expression of the 5-HT1A receptor in the raphe and limbic systems is implicated in the etiology and treatment of major depression and anxiety disorders. The rat 5-HT1A receptor gene is regulated by a proximal TATA-driven promoter and by upstream repressors that inhibit gene expression. Deletion of a 71-base pair (bp) segment between -1590/-1519 bp of the 5-HT1A receptor gene induced over 10-fold enhancement of transcriptional activity in both 5-HT1A receptor-expressing (RN46A raphe and SN48 septal) cells and receptor-negative (L6 myoblast and C6 glioma) cells. A 31-bp segment of the repressor was protected from DNase I digestion by RN46A or L6 nuclear extracts. Within the 31-bp segment, a single protein complex was present in receptor-expressing cells that bound a novel 14-bp DNA element; in receptor-negative cells, an additional complex bound an adjacent 12-bp sequence. In receptor-positive but not receptor-negative cells, mutation of the 14-bp element to eliminate protein binding abrogated repression to nearly the same extent as deletion of the -1590/-1519 bp segment. Additional mutation of both 14-bp and 12-bp elements abolished protein binding and repressor activity in receptor-negative cells. Thus a single protein-DNA complex at the 14-bp element represses the 5-HT1A receptor gene in 5-HT1A receptor-positive neuronal cells, whereas adjacent DNA elements provide a dual repression mechanism in 5-HT1A receptor-negative cells.
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PMID:Novel dual repressor elements for neuronal cell-specific transcription of the rat 5-HT1A receptor gene. 1071 39

Repetitive transcranial magnetic stimulation (rTMS) is a novel procedure which has proven effective in the treatment of major depression. We administered rTMS chronically to rats in order to determine whether this procedure affected serotonergic neurotransmission in the prefrontal cortex. Basal 5-HT levels, and the effects of challenges with the 5-HT1A receptor agonist 8-OH-DPAT and the 5-HT1B antagonist GR 127935 on 5-HT levels were determined using in vivo microdialysis. Rats which had undergone chronic rTMS showed reduced responses to both challenges, indicating subsensitivity of both the presynaptic 5-HT1A autoreceptors situated somatodendritically in the raphe nuclei and the 5-HT1B autoreceptors situated on nerve terminals. Since such subsensitivity has been demonstrated after other antidepressant treatments, our results indicate that these treatments and rTMS may have a common mechanism of action.
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PMID:Chronic repetitive transcranial magnetic stimulation induces subsensitivity of presynaptic serotonergic autoreceptor activity in rat brain. 1100 67

An enhancement of neurotransmission of serotonin (5-HT), noradrenaline, or both, underlies the antidepressant response associated with most agents presently available to treat major depression. With respect to the 5-HT system, antidepressant drugs exert immediate effects on some neuronal elements controlling overall transmission, but it is the gradual changes in neuronal responses to such treatments that are ultimately responsible for producing their therapeutic benefits. In major depression, an increase in 5-HT1A transmission is thought to be a crucial determinant of the antidepressant response, whereas an enhancement of 5-HT2 transmission in the orbitofrontal cortex may mediate the therapeutic effect of 5-HT reuptake inhibitors in obsessive-compulsive disorder (OCD). The doses of medication and the durations of treatment necessary to obtain these alterations in 5-HT transmission in various brain structures of laboratory animals are fully consistent with the conditions in the clinic necessary to attenuate symptoms in depression and OCD. It is also possible that the relief of chronic pain produced by some antidepressants may be mediated, in part, by the blockade of peripheral 5-HT2A receptors. These observations emphasize the notion that the 5-HT system is endowed with different adaptive properties in various parts of the body, which, in addition to the multiplicity of 5-HT receptors, makes this chemospecific network important in many disorders.
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PMID:Putative mechanisms of action of antidepressant drugs in affective and anxiety disorders and pain. 1121 92

The novel antidepressant mirtazapine has a dual mode of action. It is a noradrenergic and specific serotonergic antidepressant (NaSSA) that acts by antagonizing the adrenergic alpha2-autoreceptors and alpha2-heteroreceptors as well as by blocking 5-HT2 and 5-HT3 receptors. It enhances, therefore, the release of norepinephrine and 5-HT1A-mediated serotonergic transmission. This dual mode of action may conceivably be responsible for mirtazapine's rapid onset of action. Mirtazapine is extensively metabolized in the liver. The cytochrome (CYP) P450 isoenzymes CYP1A2, CYP2D6, and CYP3A4 are mainly responsible for its metabolism. Using once daily dosing, steady-state concentrations are reached after 4 days in adults and 6 days in the elderly. In vitro studies suggest that mirtazapine is unlikely to cause clinically significant drug-drug interactions. Dry mouth, sedation, and increases in appetite and body weight are the most common adverse effects. In contrast to selective serotonin reuptake inhibitors (SSRIs), mirtazapine has no sexual side effects. The antidepressant efficacy of mirtazapine was established in several placebo-controlled trials. In major depression, its efficacy is comparable to that of amitriptyline, clomipramine, doxepin, fluoxetine, paroxetine, citalopram, or venlafaxine. Mirtazapine also appears to be useful in patients suffering from depression comorbid with anxiety symptoms and sleep disturbance. It seems to be safe and effective during long-term use.
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PMID:A review of the pharmacological and clinical profile of mirtazapine. 1160 47

The role of serotonin (5-hydroxytryptamine; 5-HT) in the treatment of depressive and anxiety disorders is underscored by the therapeutic action of selective 5-HT reuptake inhibitors acting to enhance the degree of activation of various 5-HT receptor subtypes. The 5-HT1A receptors are particularly relevant to the antidepressant and anxiolytic responses in human beings. They are located presynaptically in the raphe nuclei, where they act as cell body autoreceptors to inhibit the firing rate of 5-HT neurons, and are located postsynaptically in limbic and cortical regions, where they also attenuate firing activity. The azapirones are full agonists at 5-HT1A autoreceptors and are generally, but not exclusively, partial agonists at postsynaptic 5-HT1A receptors. Some of these drugs, including gepirone and other 5-HT1A agonists such as buspirone, have been reported to exert anxiolytic and antidepressive activity in double-blind, placebo-controlled, and comparative trials. Their delayed therapeutic activity is believed to result from increased activation of postsynaptic 5-HT1A receptors occurring only after 5-HT neurons regain their normal firing activity. The recovery of this parameter, which is attributable to 5-HT1A autoreceptor desensitization, also restores 5-HT release. At this point, the summed effects of a normalized level of synaptic 5-HT and the exogenous 5-HT1A agonist can be exerted on postsynaptic 5-HT1A receptors. The widespread recognition of the clinical efficacy of such agents has largely been hampered by their undesirable pharmacokinetic properties. Most 5-HT1A agonists are indeed readily absorbed but are also rapidly eliminated, thereby often producing either suboptimal therapeutic responses at low doses, or cumbersome adverse effects at higher doses. Extended-release formulations allow once-daily dosing regimens, thus avoiding sharp peak plasma concentrations. This improves compliance and permits the use of higher dosages, which may be associated with enhanced efficacy and better tolerability relative to the immediate-release formulations. In sum, 5-HT1A receptor agonism represents a valuable and efficacious therapeutic approach to major depression.
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PMID:Is there a role for 5-HT1A agonists in the treatment of depression? 1255 51

Altered regulation of 5-HT1A receptors is implicated in mood disorders such as anxiety and major depression. To provide insight into its transcriptional regulation, we previously identified a novel DNA element [14 bp 5'-repressor element (FRE)] of the 5-HT1A receptor gene that mediates repression in neuronal and non-neuronal cells (Ou et al., 2000). We have now cloned a novel DNA binding protein [five' repressor element under dual repression binding protein-1 (Freud-1)] that binds to FRE to mediate repression of the 5-HT1A receptor or heterologous promoters. Freud-1 is evolutionarily conserved and contains two DM-14 basic repeats, a predicted helix-loop-helix DNA binding domain, and a protein kinase C conserved region 2 (C2)/calcium-dependent lipid binding (CalB) calcium/phospholipid binding domain. An intact CalB domain was required for Freud-1-mediated repression. In serotonergic raphe cells, overexpression of Freud-1 repressed the 5-HT1A promoter and decreased 5-HT1A receptor protein levels, whereas transfection of antisense to Freud-1 derepressed the 5-HT1A gene and increased 5-HT1A receptor protein expression. Calcium-dependent signaling blocked Freud-1-FRE binding and derepressed the 5-HT1A promoter. Treatment with inhibitors of calmodulin or CAM-dependent protein kinase reversed calcium-mediated inhibition of Freud-1. Freud-1 RNA and protein were present in raphe nuclei, hippocampus, cortex, and hypothalamus, and Freud-1 protein was colocalized with 5-HT1A receptors, suggesting its importance in regulating 5-HT1A receptors in vivo. Thus, Freud-1 represents a novel calcium-regulated repressor that negatively regulates basal 5-HT1A receptor expression in neurons and may play a role in the altered regulation of 5-HT1A receptors associated with anxiety or major depression.
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PMID:Freud-1: A neuronal calcium-regulated repressor of the 5-HT1A receptor gene. 1291 78

Positron emission tomography studies in major depression show reduced serotonin (5-HT)1A receptor antagonist-binding potentials in many brain regions including occipital cortex. The functional meaning of this observation in terms of signal transduction is unknown. We used postmortem brain samples from depressed suicide victims to examine the downstream effectors of 5-HT1A receptor activation. The diagnosis was established by means of psychological autopsy using Diagnostic and Statistical Manual of Mental Disorders (DSM) III-R criteria. Measurements of [35S]GTPgammaS binding to Galphai/o in the occipital cortex of suicide victims and matched controls revealed a blunted response in suicide subjects and a decrease in the coupling of 5-HT1A receptor to adenylyl cyclase. No significant group differences were detected in the expression levels of Galphai/o, Galphaq/11 or Galphas proteins, or in the activity of cAMP-dependent protein kinase A. Studies of a parallel transduction pathway downstream from 5-HT1A receptor activation demonstrated a decrease in the activity of phosphatidylinositol 3-kinase and its downstream effector Akt, as well as an increase in PTEN (phosphatase and tensin homolog deleted on chromosome 10), the phosphatase that hydrolyzes phosphatidylinositol 3,4,5-triphosphate. Finally, the activation of extracellular signal-regulated kinases 1 and 2 was attenuated in suicide victims. These data suggest that the alterations in agonist-stimulated 5-HT1A receptor activation in depressed suicide victims are also manifest downstream from the associated G protein, affecting the activity of second messengers in two 5-HT1A receptor transduction pathways that may have implications for cell survival.
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PMID:Attenuated 5-HT1A receptor signaling in brains of suicide victims: involvement of adenylyl cyclase, phosphatidylinositol 3-kinase, Akt and mitogen-activated protein kinase. 1296 65

Inhibition of serotonergic raphe neurons is mediated by somatodendritic 5-HT1A autoreceptors, which may be increased in depressed patients. We report an association of the C(-1019)G 5-HT1A promoter polymorphism with major depression and suicide in separate cohorts. In depressed patients, the homozygous G(-1019) allele was enriched twofold versus controls (p = 0.0017 and 0.0006 for G/G genotype and G allele distribution, respectively), and in completed suicide cases the G(-1019) allele was enriched fourfold (p = 0.002 and 0.00008 for G/G genotype and G allele distribution, respectively). The C(-1019) allele was part of a 26 bp imperfect palindrome that bound transcription factors nuclear NUDR [nuclear deformed epidermal autoregulatory factor (DEAF-1)]/suppressin and Hairy/Enhancer-of-split-5 (Drosophila) (Hes5) to repress 5-HT1A or heterologous promoters, whereas the G(-1019) allele abolished repression by NUDR, but only partially impaired Hes5-mediated repression. Recombinant NUDR bound specifically to the 26 bp palindrome, and endogenous NUDR was present in the major protein-DNA complex from raphe nuclear extracts. Stable expression of NUDR in raphe cells reduced levels of endogenous 5-HT1A protein and binding. NUDR protein was colocalized with 5-HT1A receptors in serotonergic raphe cells, hippocampal and cortical neurons, and adult brain regions including raphe nuclei, indicating a role in regulating 5-HT1A autoreceptor expression. Our data indicate that NUDR is a repressor of the 5-HT1A receptor in raphe cells the function of which is abrogated by a promoter polymorphism. We suggest a novel transcriptional model in which the G(-1019) allele derepresses 5-HT1A autoreceptor expression to reduce serotonergic neurotransmission, predisposing to depression and suicide.
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PMID:Impaired repression at a 5-hydroxytryptamine 1A receptor gene polymorphism associated with major depression and suicide. 1450 79

Panic disorder is a common anxiety disorder which frequently co-occurs with agoraphobia. A functional promoter polymorphism in the serotonin receptor 1A (5-HT1A) gene has been found to be associated with major depression as well as anxiety- and depression-related personality traits. We investigated a possible association between this 5-HT1A gene promoter polymorphism and panic disorder by genotyping the 1019C>G single nucleotide polymorphism in 134 panic-disorder patients with and without agoraphobia and matched 134 controls. In our sample no significant evidence of allelic association in the combined panic-disorder group was found. However, our results show a significant association with the G allele in patients with panic disorder with agoraphobia (p=0.03, n=101). In conclusion, our findings do not support a major contribution of this polymorphism to the pathogenesis of panic disorder, but provide evidence for a possible role in the subgroup with agoraphobia.
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PMID:Association of a functional 1019C>G 5-HT1A receptor gene polymorphism with panic disorder with agoraphobia. 1498 28

Selective serotonin reuptake inhibitor (SSRI) augmentation with the 5-HT1A antagonist pindolol has met with mixed results. Recent studies using positron emission tomography (PET) suggest that pindolol doses used in these studies were too low to effect 5-HT1A autoreceptor blockade. To test the hypothesis that a single higher dose of pindolol would effectively augment antidepressant responses in SSRI-refractory patients, nine subjects with major depression unresponsive to paroxetine 40 mg/day given for 2 months or more were randomized to AM pindolol 7.5 mg (n=4) or placebo (n=5). Subjects were administered the Hamilton Depression Scale (HAM-D), the Hamilton Anxiety Scale (HAM-A), the Bech-Rafaelsen Melancholia Scale, and the Zung Depression Inventory at baseline and weeks 1, 2, 3, and 4. Subjects receiving pindolol exhibited significant improvements in all ratings beginning at week 2 which continued through week 4. Aside from transient dizziness and a five-point decrease in systolic/diastolic blood pressure associated with pindolol, no adverse effects were reported. Although results must be verified in a larger sample, these findings support previous studies indicating that pindolol can accelerate antidepressant responses during SSRI therapy. In addition, results reported here suggest that a single high dose of pindolol (7.5 mg) is a more effective augmentation strategy in SSRI-refractory patients compared with the same total dose given at 2.5 mg tid.
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PMID:Once-daily high-dose pindolol for SSRI-refractory depression. 1500 31


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