Reevaluation of the regulation of beta-adrenergic receptor binding by desipramine treatment.

Treatment of rats with desipramine (DMI) has been shown to down-regulate beta-adrenergic receptor-stimulated adenylate cyclase and reduce the Bmax of beta-adrenergic receptors in some brain areas. Recent reports have indicated that the down-regulation in the number of beta-adrenergic receptors following DMI treatment does not occur if the serotonin system has been impaired following parachlorophenylalanine (PCPA) or 5,7-dihydroxytryptamine injection. We have previously shown that [3H]dihydroalprenolol ([3H]DHA), the most commonly used radioligand to measure central nervous system beta-adrenergic receptors, labels another site under normal experimental procedures, in addition to the beta-adrenergic receptors. This second site has some pharmacological characteristics of the 5-hydroxytryptamine1A receptor. The depletion of serotonin following PCPA injection was indeed able to prevent the down-regulation of [3H]DHA binding sites after DMI injection. However, PCPA alone increased the density of [3H]DHA binding sites. If the nonlinear, least squares, curve-fitting program LIGAND was allowed to define [3H]DHA nonspecific binding or if the more selective beta-adrenergic receptor radioligand [3H]CGP-1277 was used, the Bmax of beta-adrenergic receptors was not changed after PCPA injection. Importantly, PCPA did not prevent beta-adrenergic receptor down-regulation following DMI treatment. The blockade of 5-hydroxytryptamine2 receptors, via ketanserin administration, during DMI treatment did not change the response of beta-adrenergic receptors. Furthermore, if LIGAND was used to define the nonspecific binding of [3H]DHA, the down-regulation of beta-adrenergic receptors was significant 24 hr after a single DMI injection. The same rapid down-regulation was demonstrated with [3H]CGP-12177. However, if [3H]DHA was used to label beta-adrenergic receptors in the "typical" manner (nonspecific binding defined by 10 microM alprenolol), a decrease in the number of beta-adrenergic receptors was significant only after seven daily DMI injections. These data demonstrate that the use of [3H]DHA to measure beta-adrenergic receptors can be misleading, because changes in its second binding site can conceal the changes occurring in beta-adrenergic receptors. Moreover, these results suggest that a similarity in the time course of action of DMI cannot be used to support the hypothesis that its therapeutic antidepressant action is related to beta-adrenergic receptor down-regulation.