Chronic exposure of human cells in culture to the tricyclic antidepressant desipramine reduces the number of beta-adrenoceptors

Honegger, Ulrich E.; Disler, Beat; Wiesmann, Ulrich

doi:10.1016/0006-2952(86)90309-6

Cited by 53 publications

(19 citation statements)

References 14 publications

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“…Both DMI and IDZ produced a significant downregulation of 13-adrenoceptors, accompanied by a reduction in the isoproterenol-stimulated cAMP accumulation. Interestingly, the magnitude of the 13-adrenoceptor downregulation observed in the present study is similar to that induced by a variety of ADs in rat brain (Sulser 1984), and observed in other in vitro AD studies (Honegger et al 1986;Fishman and Finberg 1987;Manji et al 1991). Moreover, similar to what has been reported in rat brain (Turkka et al 1989), the [3-adrenoceptor desensitization was accompanied by a significant increase in the K, IKH ratio for the receptor.…”

Section: Idz Con Dmi "---40kdsupporting

confidence: 76%

Signal-transducing G proteins and antidepressant Drugs: Evidence for modulation of α subunit gene expression in rat brain

Lesch

Manji

1992

Biological Psychiatry

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Signal-transducing G proteins, heterotrimers formed of a, [3, and y subunits, are Psychopharmacologic research has traditionally focused on the ef,~ects of antidepressant drugs on individual neurotransmitters, and a variety of acute biochemical effects have been observed. Paralleling the recognition of the typically weeks-long latency to clinical response studies of antidepressant treatment actions have moved from a focus on disparate acute effects to an interest in possible common chronic, changes. Thus, in recent years,

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Section: Idz Con Dmi "---40kdsupporting

confidence: 76%

Signal-transducing G proteins and antidepressant Drugs: Evidence for modulation of α subunit gene expression in rat brain

Lesch

Manji

1992

Biological Psychiatry

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“…Downregulation of β 1 -adrenoceptors has been commonly used as a biological marker of antidepressant efficacy (Hancock and Marsh 1985;Honegger et al 1986;Fishman and Finberg 1987). This pharmacological effect is one of the most consistent findings after chronic administration of antidepressants (Vertulani and Sulser 1975).…”

Section: Discussionmentioning

confidence: 97%

In vitro receptor screening of pure constituents of St. John's wort reveals novel interactions with a number of GPCRs

et al. 2002

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Our present in vitro data clearly show that several pure substances in SJW are potential CNS psychoactive agents and may contribute to the antidepressant efficacy of the plant in a complex manner. Our data also reveal novel and heretofore unexpected interactions of pure compounds in SJW at a number of GPCRs, transporters, and ion channels. We hypothesize that additive or synergistic actions of different single compounds may be responsible for the antidepressant efficacy of SJW. These results and this general approach may impact our understanding of phytomedicines in general and H. perforatum specifically.

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“…Tricyclic antidepressants are well known for their potential to modulate the density of functional neurotransmitter receptors such as ␤1AR and serotonin receptors in the brain (1-3, 41, 42) as well as in cultured cells (4,9). The mechanisms for this reduction in receptor numbers are not completely understood.…”

Section: Discussionmentioning

confidence: 99%

Antidepressant-induced Switch of β1-Adrenoceptor Trafficking as a Mechanism for Drug Action

Bürgi

Baltensperger

Honegger

2003

Journal of Biological Chemistry

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Reduction in surface ␤ 1 -adrenoceptor (␤1AR) density is thought to play a critical role in mediating the therapeutic long term effects of antidepressants. Since antidepressants are neither agonists nor antagonists for G protein-coupled receptors, receptor density must be regulated through processes independent of direct receptor activation. Endocytosis and recycling of the ␤1AR fused to green fluorescent protein at its carboxylterminus (␤1AR-GFP) were analyzed by confocal fluorescence microscopy of live cells and complementary ligand binding studies. In stably transfected C6 glioblastoma cells, ␤1AR-GFP displayed identical ligand-binding isotherms and adenylyl cyclase activation as native ␤1AR. Upon exposure to isoproterenol, a fraction of ␤1AR-GFP (10 -15%) internalized rapidly and colocalized with endocytosed transferrin receptors in an early endosomal compartment in the perinuclear region. Chronic treatment with the tricyclic antidepressant desipramine (DMI) did not affect internalization characteristics of ␤1AR-GFP when challenged with isoproterenol. However, internalized receptors were not able to recycle back to the cell surface in DMI-treated cells, whereas recycling of transferrin receptors was not affected. Endocytosed receptors were absent from structures that stained with fluorescently labeled dextran, and inhibition of lysosomal protease activity did not restore receptor recycling, indicating that ␤1AR-GFP did not immediately enter the lysosomal compartment. The data suggest a new mode of drug action causing a "switch" of receptor fate from a fast recycling pathway to a slowly exchanging perinuclear compartment. Antidepressant-induced reduction of receptor surface expression may thus be caused by modulation of receptor trafficking routes.Chronic treatment with most classes of antidepressants leads to a reduction in the number of central postsynaptic ␤-adrenoceptors (␤AR) 1 in vivo and of surface ␤AR density in cell cultures (1-4). This effect is reported to be specific for the ␤ 1 -adrenoceptor subtype (5, 6). ␤AR down-regulation is accompanied by decreased receptor-stimulated cAMP formation (7). The two major effects at the molecular level become apparent in vivo after 10 -20 days of drug administration and coincide with the onset of clinical antidepressant response in humans. Therefore ␤AR down-regulation and diminished cAMP response to catecholamines may relate to the therapeutic action of antidepressants.It has been proposed that the reduction in the number of functional ␤AR could be a regulatory response to the enhanced presence of norepinephrine in the synaptic cleft after acute inhibition of norepinephrine reuptake or of monoamine oxidase activity by antidepressants (1, 8). Some clinically effective antidepressants, however, neither influence norepinephrine reuptake nor inhibit monoamine oxidase activity but still cause a ␤AR down-regulation. Furthermore, this model fails to explain the observed time lag between the rapid drug-induced increase in intrasynaptic neurotransmitter concentrations ...

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Chronic exposure of human cells in culture to the tricyclic antidepressant desipramine reduces the number of beta-adrenoceptors

Cited by 53 publications

References 14 publications

Signal-transducing G proteins and antidepressant Drugs: Evidence for modulation of α subunit gene expression in rat brain

Signal-transducing G proteins and antidepressant Drugs: Evidence for modulation of α subunit gene expression in rat brain

In vitro receptor screening of pure constituents of St. John's wort reveals novel interactions with a number of GPCRs

Antidepressant-induced Switch of β1-Adrenoceptor Trafficking as a Mechanism for Drug Action

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