5-Hydroxytryptamine2 and beta-adrenergic receptor regulation in rat brain following chronic treatment with desipramine and fluoxetine alone and in combination.

Abstract

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 beta-adrenergic and 5-hydroxytryptamine2 (5-HT2) 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 [3H]-ketanserin (5-HT2) binding, [3H]CGP-12177 (beta-adrenergic) binding, and drug level analysis. All animals receiving DMI showed significant down-regulation of 5-HT2 receptors except those receiving FLU in combination. DMI down-regulated beta-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-HT2 or beta-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.(ABSTRACT TRUNCATED AT 250 WORDS)