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.
Riva
M A
MA
Center for Molecular and Behavioral Neuroscience, Rutgers State University of New Jersey, Newark 07102.
Creese
I
I
D000818:Animals; D003891:Desipramine / Q000494:pharmacology*; D004082:Dihydroalprenolol / Q000378:metabolism; D010134:Fenclonine / Q000031:analogs & derivatives / Q000494:pharmacology; D007700:Kinetics; D008297:Male; D011412:Propanolamines / Q000378:metabolism; D051381:Rats; D011919:Rats, Inbred Strains; D011943:Receptors, Adrenergic, beta / Q000187:drug effects* / Q000378:metabolism; D011985:Receptors, Serotonin / Q000032:analysis; D012701:Serotonin / Q000502:physiology
D011412:Propanolamines; D011943:Receptors, Adrenergic, beta; D011985:Receptors, Serotonin; C020261:4-chlorophenylalanine methyl ester; D012701:Serotonin; D004082:Dihydroalprenolol; D010134:Fenclonine; C033394:CGP 12177; D003891:Desipramine