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)

1. The present study assessed the potential antidepressant action of gepirone hydrochloride, an azapirone serotonin (5-HT1A) partial agonist in patients with major depression. 2. Overall, gepirone demonstrated a significant antidepressant activity within the entire patient group (p less than 0.001). However, when subjects were stratified based upon the presence or absence of DSM III-R melancholic features, the melancholic depressives showed little change in weekly depression ratings compared to patients without melancholic symptoms (p less than 0.001). 3. Similarly, patients who were more severely ill at the pretreatment period had less improvement compared to those with more modest illness severity (p less than 0.001). 4. These observations compliment those of prior studies suggesting antidepressant activity for gepirone. 5. However, a consistent efficacy comparable to conventional neuronal reuptake inhibitor antidepressants remains to be established in patients with more severe depression characterized by melancholic features.
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PMID:Gepirone, a selective serotonin (5HT1A) partial agonist in the treatment of major depression. 135 Mar 53

Hormonal modulation of neurotransmission emerged as a concept from the recognition that adrenocortical steroids exert profound effects at the level of receptors, G-proteins and effector units. G-proteins, a family of guanine nucleotide binding regulatory components that couple neurotransmitter receptors to various types of intracellular effector systems, appear to be a key target of glucocorticoid (GC) action in the CNS. It is thought that Gs/Gi mediates stimulation/inhibition of adenylate cyclase (AC system), which forms cyclic AMP as second messenger, while receptors stimulating phospholipase C do so through Go to produce two second messengers, inositol 1,4,5-triphosphate and diacylglycerol (PI system). Recent evidence suggests that GC increase Gs alpha-and decrease Gi alpha-protein subunit expression without affecting Go alpha. Activation of central pre- and postsynaptic 5-HT1A receptors which are linked to the Gi-AC complex, induces hypothermia and ACTH/cortisol release in rodents and humans. Compared with controls, patients with a major depressive disorder exhibit increased basal cortisol secretion associated with decreased hypothermic and ACTH/cortisol responses. The attenuated neuroendocrine and thermoregulatory response to 5-HT1A receptor activation may reflect a GC-dependent feedback inhibition of the hypothalamic-pituitary-adrenal (HPA) system and subsensitivity of the presynaptic 5-HT1A-Gi-AC complex function. Differential regulation of 5-HT1A and 5-HT2 function leading to a relative 5-HT2-Go-PI complex supersensitivity may maintain HPA hyperactivity during the course of depression. These findings corroborate recent reports that GC, via GC-GC receptor (GR) complex activated promotion of gene transcription, modify the expression 5-HT1A-coupled Gi (but not 5-HT2-coupled Go) resulting in altered sensitivity of 5-HT1A-mediated signal transduction and further support the hypothesis of a differential regulation of 5-HT1A and 5-HT2 receptor function and a GC-GR/5-HT1A-G-protein--effector system-related abnormality in depression.
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PMID:The 5-HT receptor--G-protein--effector system complex in depression. I. Effect of glucocorticoids. 164 69

Serotonin (5-HT) interacts with multiple brain 5-HT receptor subtypes to influence a wide range of behaviours. Three main families of 5-HT receptors (5-HT1, 5-HT2 and 5-HT3) have been described which differ in their binding affinity for selective ligands, their receptor-effector coupling mechanisms, and the behavioural processes they regulate. Nevertheless, manipulation of several different 5-HT receptor subtypes (5-HT1A, 5-HT1C, 5-HT2 and 5-HT3) may produce anxiolytic effects; 5-HT1A and 5-HT2 receptors may be involved in the aetiology of major depression and the therapeutic effects of antidepressant treatment; and 5-HT3 receptors have been linked to reward mechanisms and cognitive processes. These advances offer therapeutic possibilities, the value of which can only be satisfactorily assessed by controlled clinical trials.
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PMID:Serotonin receptor subtypes: implications for psychopharmacology. 184 Jul 64

The 5-HT1A agonist properties of gepirone were used to test for effects on serum cortisol levels in humans, 90 min after a 10 mg oral dose. Fourteen patients with major depression were tested in a single-blind, within-subjects, placebo design. Serum cortisol levels were significantly higher 90 min after gepirone compared to placebo (p less than 0.05). Baseline Hamilton depression ratings were correlated with the serum cortisol levels after acute administration of gepirone (r = 0.54, p less than 0.05), but not placebo. Cortisol levels after a 10 mg gepirone challenge were significantly (p less than 0.02) attenuated after 3-6 weeks chronic administration of gepirone. These preliminary findings suggest that relatively low doses of gepirone may stimulate human cortisol secretion in depressed patients, and cortisol levels after gepirone challenge may correlate with depression severity. Furthermore, a desensitization to gepirone's effects on cortisol may occur after chronic gepirone administration.
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PMID:Cortisol and growth hormone responses to the 5-HT1A agonist gepirone in depressed patients. 197 5

Twenty-four patients with major depression were treated in a single-blind design with 25 mg to 75 mg gepirone, a pyrimidinyl piperidinedione analog of buspirone with serotonin1A (5-HT1A) receptor affinity properties. Twenty-four-Item Hamilton Rating Scale for Depression-(HAM-D) scores decreased by 36 percent when mean baseline scores were compared with an endpoint analysis of 6 weeks' gepirone treatment. Several subjects demonstrated marked improvements over baseline. The data are discussed within the context of 5-HT1A receptor desensitization as a potential component of antidepressant treatment.
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PMID:Gepirone as a 5-HT1A agonist in the treatment of major depression. 197 70

The electrophysiologic assessment of the action of different types of antidepressant treatments on the serotonin (5-hydroxytryptamine [5-HT]) system revealed as a common effect an enhancement of 5-HT neurotransmission, albeit each treatment achieved this result via a different mechanism. Tricyclic antidepressant drugs and electroconvulsive shock treatment sensitize postsynaptic neurons to 5-HT. Monoamine oxidase inhibitors enhance the availability of releasable 5-HT. Serotonin reuptake blockers increase the efficacy of 5-HT neurons by desensitizing 5-HT autoreceptors located on 5-HT nerve terminals. Serotonin1A receptor agonists would enhance the tonic activation of postsynaptic 5-HT1A receptors. Such results suggest that this effect of antidepressant treatments on the 5-HT system might be intimately related to their therapeutic effect in major depression.
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PMID:A role for the serotonin system in the mechanism of action of antidepressant treatments: preclinical evidence. 215

The azapirone class of anxiolytic drugs is being evaluated for clinical use in the treatment of depression. Buspirone, a serotonin (5-hydroxytryptamine, 5-HT) partial agonist active at the 5-HT1A receptor subtype, was evaluated in the treatment of depression in a series of five placebo-controlled, parallel group studies involving 382 patients with DSM-III major depression and significant associated anxiety symptoms (both Hamilton depression [HAM-D] and Hamilton anxiety [HAM-A] scales greater than or equal to 18). Buspirone therapy was initiated at 15 mg/day with individual dose titration to a maximum of 90 mg/day and resulted in marked improvement in both depressive and anxiety symptoms. Analyses of the composite data base from the five studies show significant (p less than 0.05) improvement in mean HAM-D, HAM-A, and Clinical Global Impression-Global Improvement scale ratings for buspirone-treated compared with placebo-treated patients. Of particular interest was significant improvement in cardinal depression symptoms, e.g., depressed mood, guilt, work and interest, anergia, and diurnal variation of mood. Subset analyses revealed that patients with melancholic-type major depression and patients with more severe symptoms (judged by higher initial HAM-D or HAM-A total scores) responded better to buspirone than did patients who were less ill. The buspirone dose most frequently associated with clinically significant improvement was 40 mg/day. Gepirone, an analogue of buspirone with highly selective binding affinity for the 5-HT1A receptor subtype, also shows promise of antidepressant efficacy in preliminary controlled clinical trials. These data suggest that azapirones, which as partial agonists modulate 5-HT1A receptor function, have clinically important antidepressant properties.
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PMID:Clinical effects of the 5-HT1A partial agonists in depression: a composite analysis of buspirone in the treatment of depression. 219 3

There is growing evidence that the serotonergic (5-HT) system is involved in the pathogenesis and treatment of major depression. The 5-HT receptor subtype involved in the enhancing effect of antidepressant treatments, however, has not been identified. The present study was undertaken to quantify 5-HT1A sites in the rat brain by autoradiography and membrane binding, using the selective ligand [3H]8-hydroxy-N,N-dipropyl-2-aminotetralin (8-OH-DPAT), following long-term antidepressant treatment. Following a 21-day treatment with amitriptyline (10 mg/kg/day), there was a significant increase of [3H]8-OH-DPAT binding measured by autoradiography in the dorsal hippocampus, but there was no change in the nucleus raphe dorsalis; whole brain membrane binding revealed an increase in the number of binding sites, with no change in the affinity for [3H]8-OH-DPAT. Conversely, fluoxetine (10 mg/kg/day), a selective blocker of 5-HT reuptake, and gepirone (10 mg/kg/day), a 5-HT1A agonist, both administered for 21 days, significantly reduced [3H]8-OH-DPAT binding measured by autoradiography in the nucleus raphe dorsalis without altering hippocampal binding sites. The control active treatment with diazepam (2 mg/kg/day) did not alter [3H]8-OH-DPAT binding in the hippocampus or in the nucleus raphe dorsalis. All groups were compared to a 21-day vehicle-treated control group. These results are fully consistent with previous electrophysiological and behavioral studies and suggest that alterations of 5-HT1A receptors might underlie the enhancement of 5-HT neurotransmission by antidepressant treatments.
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PMID:Autoradiographic quantification of serotonin1A receptors in rat brain following antidepressant drug treatment. 253 23

The cortisol response to ipsapirone (a 5-HT1A-partial agonist that produces a dose-dependent increase in plasma cortisol secretion in man) is blunted in major depression. Buspirone is another 5-HT1A agonist that increases cortisol secretion in man. This study investigated cortisol and prolactin (PRL) responses to buspirone (30 mg orally) in 45 major depressed subjects and 28 normal controls. Buspirone administration yielded a significant increase in cortisol and PRL levels in both normal controls and depressed subjects. No differences in buspirone-induced hormone responses were found either between major depressives and normal controls or between melancholic and nonmelancholic depressives. There were no significant relationships between severity of depression and any of the hormonal responses to buspirone. PRL responses to buspirone were significantly higher in women than in men.
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PMID:Effects of buspirone on plasma prolactin and cortisol levels in major depressed and normal subjects. 801

Chronic administration of antidepressant drugs enhances synaptic serotonergic transmission. Nefazodone, a member of a new class of antidepressants, has a pharmacologic profile that is distinct from the first-generation agents (e.g., tricyclics and monoamine oxidase inhibitors) as well as the more selectively acting second-generation agents (e.g., serotonin or norepinephrine uptake inhibitors, and serotonin type 1A partial agonists). Nefazodone acts both as a 5-HT2 receptor antagonist and as a serotonin (5-HT) reuptake inhibitor. Nefazodone's potent 5-HT2 antagonism in combination with 5-HT reuptake inhibition appears to enhance 5-HT1A-mediated neurotransmission. Nefazodone has very selective serotonergic effects, with negligible affinity for cholinergic and histamine receptors and low affinity for alpha 1-adrenergic receptors. It is also free of cardiotoxicity and is well tolerated even at high doses. The two primary effects on serotonergic neurotransmission, 5-HT2 antagonism and 5-HT reuptake inhibition, are thought to contribute importantly to nefazodone's therapeutic efficacy and clinical utility. It is postulated that 5-HT2 antagonism dampens the activating side effects experienced by some patients when treated with existing 5-HT reuptake inhibitors. Nefazodone's effectiveness as an antidepressant drug has been shown in a series of well-controlled, placebo-comparison studies of somewhat differing designs involving patients with major depression. In placebo-controlled studies comparing nefazodone and the tricyclic antidepressant imipramine, the drugs produced comparable and significant therapeutic benefit. Nefazodone is associated with fewer adverse events than imipramine. Nefazodone lacks the troublesome anticholinergic side effects of tricyclic antidepressants, as well as serotonergic/noradrenergic-mediated effects.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Novel serotonergic mechanisms and clinical experience with nefazodone. 813 Nov 54


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