Dual aminergic regulation of central beta adrenoceptors. Effect of "atypical" antidepressants and 5-hydroxytryptophan.
Nonlinear regression analysis of agonist competition binding curves reveals that the [3H]-dihydroalprenolol-labeled receptor population with low affinity for isoproterenol is increased by p-chlorophenylalanine (PCPA) and this increase is abolished by 5-hydroxytryptophan (5-HTP) in vivo. Desipramine (DMI) decreased the beta adrenoceptor population with high agonist affinity to the same degree in PCPA-treated animals as in control animals, thus explaining the reported discrepancy between beta adrenoceptor number and responsiveness of the beta adrenoceptor-coupled adenylate cyclase system. Mianserin also selectively reduced the beta adrenoceptor population with high agonist affinity in membrane preparations of normal animals, whereas fluoxetine selectively abolished the upregulation of the low affinity sites in reserpinized animals and had no effect on either receptor population from brain of normal animals. The results emphasize the importance of nonlinear regression analysis of agonist competition binding for the interpretation of drug action and encourage the pursuit of the molecular neurobiology of the serotonin (5-HT)/norepinephrine (NE) link in brain.
Manier
D H
DH
Department of Pharmacology, Vanderbilt University School of Medicine, Nashville, TN 37232.
Gillespie
D D
DD
Sulser
F
F
D006916:5-Hydroxytryptophan / Q000494:pharmacology*; D000318:Adrenergic beta-Agonists / Q000378:metabolism / Q000494:pharmacology; D000818:Animals; D000928:Antidepressive Agents / Q000494:pharmacology; D001667:Binding, Competitive / Q000187:drug effects; D003891:Desipramine / Q000494:pharmacology; D004082:Dihydroalprenolol / Q000378:metabolism; D005473:Fluoxetine / Q000494:pharmacology; D008297:Male; D008803:Mianserin / Q000494:pharmacology; D008954:Models, Biological; D051381:Rats; D011919:Rats, Inbred Strains; D011943:Receptors, Adrenergic, beta / Q000187:drug effects*; D012044:Regression Analysis; D012110:Reserpine / Q000494:pharmacology; D012701:Serotonin / Q000502:physiology; D012702:Serotonin Antagonists / Q000494:pharmacology; D014316:Tritium
D000318:Adrenergic beta-Agonists; D000928:Antidepressive Agents; D011943:Receptors, Adrenergic, beta; D012702:Serotonin Antagonists; D005473:Fluoxetine; D014316:Tritium; D008803:Mianserin; D012701:Serotonin; D004082:Dihydroalprenolol; D012110:Reserpine; D006916:5-Hydroxytryptophan; D003891:Desipramine