5-HYDROXYTRYPTAMINE(2) AND BETA-ADRENERGIC-RECEPTOR REGULATION IN RAT-BRAIN FOLLOWING CHRONIC TREATMENT WITH DESIPRAMINE AND FLUOXETINE ALONE AND IN COMBINATION

A chronic (14-day) study was initiated to investigate the effects of c ombined fluoxetine (FLU) and desipramine (DMI) treatment on the densit ies and affinities of beta-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 m g/kg/day; FLU, 10 mg/kg/day, plus DMI, 5 mg/kg/day; or vehicle (distil led water). After 14 days the cortex was dissected out and used for [H -3]-ketanserin (5-HT2) binding, [H-3]CGP-12177 (beta-adrenergic) bindi ng, and drug level analysis. All animals receiving DMI showed signific ant down-regulation of 5-HT2 receptors except those receiving FLU in c ombination. DMI down-regulated beta-adrenergic receptors in a dose-dep endent manner, with significantly greater down-regulation seen with th e combination than with DMI (5 mg/kg/day) alone. This latter effect wa s apparently the result of greater levels of DMI in cortex with the co mbination than with DMI (5 mg/kg/day) alone. FLU had no effect on 5-HT 2 or beta-adrenergic receptors on its own. Coadministration of FLU and DMI resulted in a doubling of levels of FLU and its demethylated meta bolite, norfluoxetine (NFLU), and a tripling of DMI levels compared wi th values observed when FLU(10 mg/kg/day) or DMI (5 mg/kg/day) was adm inistered alone. These results suggest that with the DMI/FLU combinati on (a) FLU and/or NFLU block the down-regulation of 5-HT2 receptors ca used by DMI alone, (b) an important factor determining beta-adrenergic receptor density may be the elevated DMI levels relative to those wit h DMI (5 mg/kg/day) alone, (c) FLU and/or NFLU inhibit the metabolism of DMI, and (d) DMI inhibits the metabolism of FLU.