Preclinical evaluation of the putative antidepressant nefazodone

Autor: David L. Knight, Kenneth C. Dole, Michael J. Owens, Charles B. Nemeroff
Rok vydání: 1993
Předmět:
Zdroj: Depression. 1:315-323
ISSN: 1522-7162
1062-6417
Popis: The effects of the putative antidepressant, nefazodone, which possesses prominent 5-HT2 antagonist properties and moderate 5-HT uptake inhibition activity, on several neurochemical measures commonly observed in clinically efficacious antidepressants and serotonergic agents were evaluated. These include: (1) the number of β-adrenergic and 5-HT2 receptors and (2) measures of hypothalamic-pituitary-adrenal axis function. Chronic administration of nefazodone at clinically relevant doses resulted in small but significant decreases in the density of cortical 5-HT2 and β-adrenergic receptors. Moreover, chronic nefazodone administration resulted in an increase in cortical CRF receptor number. Acute administration of nefazodone (1-100 mg/kg sc) did not alter plasma ACTH concentrations. Only the 100 mg/kg dose increased plasma corticosterone concentrations. Like nefazodone, acute administration of the selective 5-HT2 antagonist ketanserin (1.5-10 mg/kg) did not alter plasma ACTH or corticosterone concentrations. Neither acute (3.3 mg/kg sc) nor chronic (33.3 mg/kg/day × 28 days) administration of nefazodone altered the regional brain concentration of corticotropin-releasing factor (CRF) in any of 10 brain regions examined. These data suggest that the 5-HT2 antagonist properties of nefazodone are sufficient to inhibit any stimulation of HPA axis activity that may result from the drugs' inherent agonist activity (i.e., 5-HT uptake inhibition and agonist activity of its metabolite m CPP). Moreover, chronic administration of nefazodone at a dose which produces down regulation of conical 5-HT2 and β-adrenergic receptors, an effect commonly observed after administration of other clinically effective antidepressants, increased cortical CRF receptor binding density, possibly the result of diminished extra-hypothalamic CRF release. These data, taken together, provide further neurochemical evidence for the purported antidepressant effects of nefazodone. Depression 1:315-323 (1993). © 1993 Wiley-Liss, Inc.
Databáze: OpenAIRE
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