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)

Recent pharmacologic studies suggest that nefazodone may possess antidepressant activity. Nefazodone is active in behavioral models predictive of antidepressant potential. It is active in reversing learned helplessness, prevents reserpine-induced ptosis, and enhances response efficiency in the differential reinforcement for low rates of response paradigm. In in vitro studies, nefazodone inhibits the binding of [3H]ketanserin to cortical serotonin2 (5-HT2) binding sites, whereas in vivo, it antagonizes the 5-HT2-mediated quipazine-induced head shake in rats. In ex vivo studies, acute oral administration of nefazodone inhibits cortical serotonin uptake and occupies frontal cortical 5-HT2 receptor binding sites. Chronic administration of nefazodone produces a reduction in 5-HT2-mediated behavior and decreases cortical 5-HT2 receptor binding site density. Further, a chronic high-dose nefazodone regimen significantly potentiates 5-HT1A-mediated behavioral responses in rats. Nefazodone exhibits decreased anticholinergic, alpha-adrenolytic, and sedative activity relative to other antidepressants.
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PMID:Nefazodone: preclinical pharmacology of a new antidepressant. 227 30

Nefazodone is a new antidepressant drug with a pharmacologic profile distinct from that of the tricyclic, monoamine oxidase inhibitor, and serotonin selective reuptake inhibitor antidepressants. Nefazodone was initially discovered for its ability to block 5-HT2A receptors and its reduced potency as an alpha 1-adrenergic blocker. It was later shown to inhibit both serotonin and norepinephrine uptake in vitro, attributes which most likely impart its clinical efficacy and which differentiate nefazodone from its chemical predecessor trazodone. The combination of these two mechanisms may ultimately result in a facilitation of 5-HT1A-mediated neurotransmission, which may be beneficial for treating symptoms of depression as evidenced by recent clinical findings. In addition, the preclinical profile of nefazodone demonstrates that it has decreased anticholinergic and antihistaminic activity relative to traditional agents. Clinical findings to date are consistent with these observations.
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PMID:Pharmacology and neurochemistry of nefazodone, a novel antidepressant drug. 1081 10

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

The chemistry, pharmacology, pharmacokinetics, and clinical efficacy of nefazodone hydrochloride, a new antidepressant, are described. Nefazodone enhances serotonin (5-hydroxytryptamine [5-HT]) synaptic transmission by acting as an antagonist at 5-HT2 receptors and by inhibiting the reuptake of 5-HT. These two mechanisms combined may enhance 5-HT1A-mediated transmission. In addition, nefazodone weakly inhibits the reuptake of norepinephrine. Nefazodone is a structural analogue of trazodone but is pharmacologically distinct. In placebo-controlled trials, nefazodone was as effective as imipramine for the treatment of major depression and produced clinical benefits in patients with depression-related anxiety and sleep disturbances. More than 2000 patients have received nefazodone in clinical trials. The most commonly reported adverse drug reactions (ADRs) are asthenia, somnolence, dry mouth, nausea, constipation, dizziness, lightheadedness, confusion, abnormal vision, and blurred vision. The incidence of sexual-dysfunction ADRs may be less than that reported for other antidepressants. Nefazodone does not inhibit rapid-eye movement sleep. Nefazodone, an inhibitor of the hepatic P-450 isoenzyme CYP3A4, may increase concentrations of drugs metabolized by this isoenzyme, such as terfenadine, astemizole, triazolam, alprazolam, and midazolam. Caution should be exercised in administering nefazodone hydrochloride with triazolobenzodiazepines, and coadministration with terfenadine or astemizole is contra-indicated. The dosage should start at 100 mg twice daily and then be increased, depending on occurrence of ADRs and the patient's clinical response, to 300-600 mg daily. In elderly or debilitated patients, the initial dosage should be half the usual dosage. Nefazodone hydrochloride is as effective as other available antidepressants and may cause fewer ADRs.
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PMID:Nefazodone: a new antidepressant. 889 78

Animal experimental studies suggest that the therapeutic effect of selective serotonin re-uptake inhibitors (SSRIs) may involve neuroadaptive changes in pre- and post-synaptic serotonin1A (5-HT1A) receptors. We used the endocrine and hypothermic responses to the 5-HT1A receptor agonist, gepirone (20 mg orally), to assess 5-HT1A receptor sensitivity in 37 healthy male volunteers who were studied before and following random double-blind, allocation to treatment with paroxetine, nefazodone or placebo for 17 days. Following antidepressant drug treatment, hypothermic responses to gepirone were markedly decreased by paroxetine but only slightly diminished by nefazodone. Paroxetine also lowered the growth hormone and cortisol responses to gepirone. There was no change in either hypothermic or endocrine response following placebo treatment. Our results suggest that paroxetine treatment produces a striking attenuation of measures of both pre- and post-synaptic 5-HT1A receptor function. Nefazodone appears to decrease the sensitivity of 5-HT1A autoreceptors to some extent and this effect may contribute to its antidepressant activity.
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PMID:Effect of paroxetine and nefazodone on 5-HT1A receptor sensitivity. 929 30