Article

Rapid down regulation of β-adrenoceptors by co-administration of desipramine and fluoxetine

Merrell Dow Research Institute, Cincinnati, OH 45215.
European Journal of Pharmacology (Impact Factor: 2.68). 10/1988; 154(2):125-34. DOI: 10.1016/0014-2999(88)90089-1
Source: PubMed

ABSTRACT Co-administration of desipramine and fluoxetine resulted in a 27% decline in cerebral cortical beta-adrenoceptor density after four days - a time point at which neither agent alone was effective. After 14 days, desipramine- and desipramine + fluoxetine-treated rats showed decreased receptor levels, with a greater decrement seen with the combined treatment. Fluoxetine, alone, had no affect on beta-adrenoceptor density at any time point examined. These effects are attributable to central serotonergic action since they were prevented by prior treatment with p-chlorophenylalanine. Cyproheptadine, a 5-HT2 antagonist, did not block these effects. Independent administration of fluoxetine and desipramine produced approximately 20% decrement in isoproterenol-stimulated cyclic AMP accumulation after four days of treatment. Co-administration of desipramine and fluoxetine resulted in a 35% decrement in cyclic AMP accumulation which was nearly additive with that produced by either drug alone. Consequently, the combination of a norepinephrine and serotonin uptake inhibitor may be an advantageous and rapid treatment for the alleviation of certain forms of depression.

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    • "Only one of the three studies finding evidence for up-regulation of 5-HT 2A receptor-binding sites confirmed the widely replicated result for imipramine-induced down-regulation of 5-HT 2A receptors [14] [17] [19]. Six of the eight studies finding no change in 5-HT 2A receptor binding did find positive effects with a tricyclic antidepressant comparator drug [35] [2] [5] [15] [16] [42]. One of the two negative studies which did not examine other positive comparator antidepressant drugs, however, did measure both [ 125 I]DOI binding to the agonist site and [ 3 H]ketanserin binding to the antagonist site [22]. "
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    • "We examined the down-regulation of b-adrenergic receptors in the hippocampus as a marker of the neuroadaptative changes induced by repeated administration of classical antidepressant drugs, such as tricyclic antidepressants and monoamine oxidase inhibitors (reviewed by Weiss et al. 1982; Racagni et al. 1983). It must be emphasized that this is only a marker of neuroadaptation and not a biochemical correlate of antidepressant medication because fluoxetine and other selective serotonin reuptake inhibitor antidepressants fail to down-regulate b-adrenergic receptors (unless they are combined with imipramine or desipramine) (Maggi et al. 1980; Wong et al. 1985; Baron et al. 1988; Beasley et al. 1992; Goodnough and Baker 1994; Palvimaki et al. 1994; but see Byerley et al. 1988 for different results), and b-adrenergic receptor antagonists are known to induce depression (reviewed by Patten and Barbui 2004). The development of imipramine-induced down-regulation of b-adrenergic receptors is slower in hippocampus than in cerebral cortex (Duncan et al. 1994). "
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