Design of a desipramine dosing regimen for the rapid induction and maintenance of maximal cortical beta-adrenoceptor downregulation.
Chronic administration of desipramine to rats causes a gradual reduction in cortical beta-adrenoceptor density. We examined the relationship between the duration of treatment with desipramine, and the rate and intensity of cortical beta-adrenoceptor downregulation. Male Sprague-Dawley rats were administered a 3.75 mg/kg/12 hr dose of desipramine for 4, 8 or 16 days. After 4 and 8 days of treatment, cortical beta-adrenoceptor density was reduced by 14 and 26% respectively. After 16 days of treatment, cortical beta-adrenoceptor density was maximally reduced by 36%. In our next series of experiments, we tested the hypothesis that the dose of desipramine required to rapidly induce maximal beta-adrenoceptor downregulation was higher than the dose required to maintain maximal beta-adrenoceptor downregulation. Initially, cortical beta-adrenoceptors were rapidly, and maximally downregulated with a four day, 10 mg/kg/12 hr induction regimen of desipramine. Trough, steady-state brain/cortical concentrations of desipramine plus desmethyldesipramine at the end of this regimen were approx 4000 ng/gm. Subsequently, maintenance desipramine regimens of 3.75 mg/kg/12 hr and 1.87 mg/kg/12 hr or vehicle were initiated for the next four days. Inspite of a 20-fold drop in brain/cortical concentrations of desipramine plus its metabolite, the 3.75 mg/kg maintenance regimen sustained maximal cortical beta-adrenoceptor downregulation. The 1.87 mg/kg maintenance regimen did result in a marked (25%) but non-significant recovery in the density of beta-adrenoceptors. Animals administered a vehicle maintenance regimen showed a large (50%) and statistically significant recovery of cortical beta-adrenoceptor density.
Department of Pharmaceutics, Philadelphia College of Pharmacy and Science, PA 19104.
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D'Mello
D000818:Animals; D001921:Brain / Q000187:drug effects / Q000378:metabolism; D002540:Cerebral Cortex / Q000187:drug effects / Q000378:metabolism*; D003891:Desipramine / Q000008:administration & dosage* / Q000493:pharmacokinetics / Q000494:pharmacology*; D015536:Down-Regulation / Q000187:drug effects*; D007099:Imipramine / Q000031:analogs & derivatives / Q000097:blood / Q000378:metabolism; D008297:Male; D051381:Rats; D017207:Rats, Sprague-Dawley; D011943:Receptors, Adrenergic, beta / Q000187:drug effects*
D011943:Receptors, Adrenergic, beta; C036691:didesipramine; D007099:Imipramine; D003891:Desipramine