Rapid down regulation of beta-adrenoceptors by co-administration of desipramine and fluoxetine.
Co-administration of desipramine and fluoxetine resulted in a 27% decline in cerebral cortical beta-adrenoceptor density after four days - a time point at which neither agent alone was effective. After 14 days, desipramine- and desipramine + fluoxetine-treated rats showed decreased receptor levels, with a greater decrement seen with the combined treatment. Fluoxetine, alone, had no affect on beta-adrenoceptor density at any time point examined. These effects are attributable to central serotonergic action since they were prevented by prior treatment with p-chlorophenylalanine. Cyproheptadine, a 5-HT2 antagonist, did not block these effects. Independent administration of fluoxetine and desipramine produced approximately 20% decrement in isoproterenol-stimulated cyclic AMP accumulation after four days of treatment. Co-administration of desipramine and fluoxetine resulted in a 35% decrement in cyclic AMP accumulation which was nearly additive with that produced by either drug alone. Consequently, the combination of a norepinephrine and serotonin uptake inhibitor may be an advantageous and rapid treatment for the alleviation of certain forms of depression.
Baron
B M
BM
Merrell Dow Research Institute, Cincinnati, OH 45215.
Ogden
A M
AM
Siegel
B W
BW
Stegeman
J
J
Ursillo
R C
RC
Dudley
M W
MW
D000255:Adenosine Triphosphate / Q000378:metabolism; D000818:Animals; D002540:Cerebral Cortex / Q000187:drug effects / Q000378:metabolism; D000242:Cyclic AMP / Q000378:metabolism; D003891:Desipramine / Q000494:pharmacology*; D004082:Dihydroalprenolol; D005473:Fluoxetine / Q000494:pharmacology*; D006897:Hydroxyindoleacetic Acid / Q000378:metabolism; D066298:In Vitro Techniques; D008297:Male; D051381:Rats; D011919:Rats, Inbred Strains; D011943:Receptors, Adrenergic, beta / Q000187:drug effects*; D012701:Serotonin / Q000378:metabolism
D011943:Receptors, Adrenergic, beta; D005473:Fluoxetine; D012701:Serotonin; D006897:Hydroxyindoleacetic Acid; D004082:Dihydroalprenolol; D000255:Adenosine Triphosphate; D000242:Cyclic AMP; D003891:Desipramine