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: 2.53). 10/1988; 154(2):125-34. DOI: 10.1016/0014-2999(88)90089-1
Source: PubMed


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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    ABSTRACT: Down-regulation of 5-hydroxytryptamine(2A) (5-HT(2A)) receptors has been a consistent effect induced by most antidepressant drugs. The evidence for down-regulation of 5-HT(2A) receptor binding following subchronic treatment with fluoxetine and other selective serotonin reuptake inhibitors (SSRIs) is mixed. The question of 5-HT(2A) receptor sensitivity during chronic administration of antidepressants is important since activation of 5-HT(2A) receptors is associated with impulsivity. Continued activation of 5-HT(2A) receptors may functionally oppose activation of other non-5-HT(2A) receptors in the prefrontal cortex associated with the clinical efficacy of SSRI treatment. Therefore, the effects of repeated daily administration of fluoxetine (10 mg/kg, i.p. x 3 weeks) on pharmacologically characterized electrophysiological response mediated by 5-HT(2A) receptor activation, 5-HT-induced excitatory postsynaptic currents (EPSCs), in rat prefrontal cortical slices was examined. The concentration-response curve for 5-HT-induced EPSCs was unchanged following subchronic fluoxetine treatment. This subchronic fluoxetine treatment failed to modify electrophysiological responses to AMPA in layer V pyramidal cells as well. These findings would be consistent with the hypothesis that blockade of 5-HT(2A) receptors may enhance the effects of SSRIs or serotonin/norepinephrine reuptake inhibitors (SNRIs).
    Full-text · Article · Jul 2008 · Neuroscience Letters
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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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    ABSTRACT: Antidepressant drugs have a clinical latency that correlates with the development of neuroadaptive changes, including down-regulation of beta-adrenergic receptors in different brain regions. The identification of drugs that shorten this latency will have a great impact on the treatment of major depressive disorders. We report that the time required for the antidepressant imipramine to reduce the expression of beta-adrenergic receptors in the hippocampus is reduced by a co-administration with centrally active ligands of type 2/3 metabotropic glutamate (mGlu2/3) receptors. Daily treatment of mice with imipramine alone (10 mg/kg, i.p.) reduced the expression of beta-adrenergic receptors in the hippocampus after 21 days, but not at shorter times, as assessed by western blot analysis of beta1-adrenergic receptors and by the amount of specifically bound [3H]CGP-12177, a selective beta-adrenergic receptor ligand. Down-regulation of beta-adrenergic receptors occurred at shorter times (i.e. after 14 days) when imipramine was combined with low doses (0.5 mg/kg, i.p.) of the selective mGlu2/3 receptor agonist LY379268, or with the preferential mGlu2/3 receptor antagonist LY341495 (1 mg/kg, i.p.). Higher doses of LY379268 (2 mg/kg, i.p.) were inactive. This intriguing finding suggests that neuroadaptation to imipramine--at least as assessed by changes in the expression of beta1-adrenergic receptors--is influenced by drugs that interact with mGlu2/3 receptors and stimulates further research aimed at establishing whether any of these drugs can shorten the clinical latency of classical antidepressants.
    Preview · Article · Jul 2005 · Journal of Neurochemistry
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