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5‐Hydroxytryptamine 2 and β‐Adrenergic Receptor Regulation in Rat Brain Following Chronic Treatment with Desipramine and Fluoxetine Alone and in Combination
Author(s) -
Goodnough D. B.,
Baker G. B.
Publication year - 1994
Publication title -
journal of neurochemistry
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.75
H-Index - 229
eISSN - 1471-4159
pISSN - 0022-3042
DOI - 10.1046/j.1471-4159.1994.62062262.x
Subject(s) - desipramine , fluoxetine , pharmacology , adrenergic , adrenergic receptor , neuroscience , medicine , endocrinology , receptor , chemistry , antidepressant , hippocampus , biology , serotonin
A chronic (14‐day) study was initiated to investigate the effects of combined fluoxetine (FLU) and desipramine (DMI) treatment on the densities and affinities of β‐adrenergic and 5‐hydroxytryptamine 2 (5‐HT 2 ) receptors. Male Sprague‐Dawley rats were administered the following doses using osmotic minipumps: FLU, 10 mg/kg/day; DMI, 5, 10, or 15 mg/kg/day; FLU, 10 mg/kg/day, plus DMI, 5 mg/kg/day; or vehicle (distilled water). After 14 days the cortex was dissected out and used for [ 3 H]‐ketanserin (5‐HT 2 ) binding, [ 3 H]CGP‐12177 (β‐adrenergic) binding, and drug level analysis. All animals receiving DMI showed significant down‐regulation of 5‐HT 2 receptors except those receiving FLU in combination. DMI down‐regulated β‐adrenergic receptors in a dose‐dependent manner, with significantly greater down‐regulation seen with the combination than with DMI (5 mg/kg/day) alone. This latter effect was apparently the result of greater levels of DMI in cortex with the combination than with DMI (5 mg/kg/day) alone. FLU had no effect on 5‐HT 2 or β‐adrenergic receptors on its own. Coadministration of FLU and DMI resulted in a doubling of levels of FLU and its demethylated metabolite, norfluoxetine (NFLU), and a tripling of DMI levels compared with values observed when FLU (10 mg/kg/day) or DMI (5 mg/kg/day) was administered alone. These results suggest that with the DMI/FLU combination (a) FLU and/or NFLU block the down‐regulation of 5‐HT 2 receptors caused by DMI alone, (b) an important factor determining β‐adrenergic receptor density may be the elevated DMI levels relative to those with DMI (5 mg/kg/day) alone, (c) FLU and/or NFLU inhibit the metabolism of DMI, and (d) DMI inhibits the metabolism of FLU.