Serotonergic neurons do not influence the regulation of beta adrenoceptors induced by either desipramine or isoproterenol

J. G. Hensler, G. A. Ordway, C. Gambarana, P. Areso, A. Frazer

Research output: Contribution to journalArticlepeer-review

15 Scopus citations

Abstract

It has been suggested that 5-hydroxytryptamine (serotonin)-containing neurons influence the regulation of central beta adrenoceptors caused by antidepressants. [3H]Dihydroalprenolol ([3H]DHA) was the radioligand used in these previous studies to measure beta adrenoceptors. In this study, we compared the binding characteristics of [3H]DHA with those of [125I]iodopindolol ([125I]IPIN) and used [125I]IPIN to study effects of lesioning serotonergic nerves on the regulation of beta adrenoceptors. A comparison was made in homogenates prepared from rat frontal cortex of the specific binding of [3H]DHA with that of [125I]IPIN to beta adrenoceptors. Nonlinear regression analysis of saturation experiments of [3H]DHA binding to cortical homogenates indicated that a two-component binding model fit the data significantly better than a one-component model. A dissociation constant value of 0.47 ± 0.16 nM and a B(max) value of 62 ± 7 fmol/mg protein were obtained for the high-affinity site. The low-affinity site was poorly defined. Rosenthal transformations of the saturation isotherms for [3H]DHA binding were clearly curvilinear. By contrast, nonlinear regression analysis of saturation experiments of the binding of [125I]IPIN indicated that the binding of this radioligand was described adequately by a one-component model and yielded a dissociation constant value of 147 ± 10 pM with a B(max) of 80 ± 5 fmol/mg protein. Rosenthal transformations of the [125I]IPIN data were linear. From such data, it was inferred that [3H]DHA binds to some site in addition to beta adrenoceptors, whereas [125I]IPIN does not. In frontal cortical homogenates of rats treated with 5,7-dihydroxytryptamine (5,7-DHT), the density of specific binding sites for [3H]DHA was significantly increased, whereas no increase in the specific binding of [125I]IPIN was observed. Moreover, when [125I]IPIN was used as the ligand to measure beta adrenoceptors, lesioning serotonergic neurons with 5,7-DHT did not prevent the down-regulation of beta adrenoceptors induced by chronic administration of desipramine. Furthermore, as assessed by quantitative autoradiography using [125I]IPIN, the down-regulation of subtypes of beta adrenoceptors in different regions of brain, produced by chronic intraventricular infusion of the direct acting agonist isoproterenol, was not altered in rats pretreated with 5,7-DHT. We conclude that 5,7-DHT-induced lesioning of serotonergic neurons does not influence the down-regulation of beta adrenoceptors as a result of repeated administration of the tricyclic antidepressant desipramine or chronic infusion of the agonist isoproterenol when [125I]IPIN is used as the radioligand to measure these receptors. Interestingly, treatment of rats with 5,7-DHT resulted in a significant reduction in the binding of [125I]IPIN to beta1 adrenoceptors in nine of 13 areas of the brain examined and a significant reduction in beta2 adrenoceptors in five of the areas, suggesting the presence of beta adrenoceptors on serotonergic neurons in many areas of the brain.

Original languageEnglish (US)
Pages (from-to)656-664
Number of pages9
JournalJournal of Pharmacology and Experimental Therapeutics
Volume256
Issue number2
StatePublished - 1991

ASJC Scopus subject areas

  • Molecular Medicine
  • Pharmacology

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