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

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.