In vivo effects of the simultaneous blockade of serotonin and norepinephrine transporters on serotonergic function. Microdialysis studies.
The effects of the blockade of serotonin (5-HT) and norepinephrine (NE) transporters on extracellular 5-HT (5-HText) have been examined using in vivo microdialysis in conscious rats. Locally infused, imipramine increased 5-HText dose-dependently in raphe nuclei and frontal cortex. The potency was identical (ED50 11 microM), although greater elevations were noted in the raphe nuclei (e.g., 74.5 +/- 16.9 vs. 41.1 +/- 4.5 fmol/fraction in the frontal cortex at 33 microM imipramine). The i.p. administration of imipramine at 4, 10 and 20 mg/kg increased 5-HText dose-dependently in the frontal cortex to concentrations as high as 390% of basal values. The lowest dose of imipramine significantly increased 5-HText in the raphe, but not in the frontal cortex (187 vs. 120% of basal values, respectively), but higher doses did not cause substantially greater increases in the raphe. The lowest dose affected 5-HText in a manner comparable to 1 mg/kg of the selective 5-HT reuptake inhibitors citalopram and fluvoxamine. The noradrenergic system may participate in the cortical elevations seen after 10 and 20 mg/kg of imipramine, because 10 mg/kg of desipramine significantly increased 5-HText in the frontal cortex, but not the raphe nuclei, of fluoxetine-treated rats (from 8.6 +/- 1.4 to 13.3 +/- 1.9 fmol/fraction; prefluoxetine values: 4.3 +/- 0.6 fmol/fraction, n = 11). Desipramine alone (10 mg/kg i.p.) did not modify 5-HText in the frontal cortex. The elevation induced by desipramine in fluoxetine-treated rats does not seem to involve changes in the activation of alpha-2 adrenoceptors, as it was still present in rats pretreated with 0.2 mg/kg i.p. of RX-821002, a selective antagonist of alpha-2 adrenoceptors. Moreover, clonidine, an alpha-2 adrenoceptor agonist, significantly reduced 5-HText in fluoxetine-treated rats when infused locally in the cortex, but it did not modify the effects of the systemic administration of desipramine, providing a further indication that alpha-2 heteroreceptors in 5-HT terminals do not participate in the effects of desipramine. When given for 2 weeks, 4 mg/kg day of imipramine significantly elevated 5-HText in the frontal cortex (from 7.7 +/- 1.2 to 20.0 +/- 5.8 fmol/fraction), but not in the raphe nuclei. These results are consistent with previous data suggesting that low doses of antidepressants with serotonergic action enhance 5-HText in the frontal cortex only after repeated treatment. The elevations noted in the frontal cortex after the higher doses of imipramine may reflect the involvement of the noradrenergic system.
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Department of Neurochemistry, Consejo Superior de Investigaciones Cientificas, Barcelona, Spain.
Artigas
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D018759:Adrenergic Uptake Inhibitors / Q000494:pharmacology; D000818:Animals; D002352:Carrier Proteins / Q000037:antagonists & inhibitors; D002540:Cerebral Cortex / Q000378:metabolism*; D015283:Citalopram / Q000494:pharmacology; D003000:Clonidine / Q000494:pharmacology; D003891:Desipramine / Q000494:pharmacology; D005473:Fluoxetine / Q000494:pharmacology; D016666:Fluvoxamine / Q000494:pharmacology; D007099:Imipramine / Q000494:pharmacology*; D008297:Male; D008562:Membrane Glycoproteins / Q000037:antagonists & inhibitors; D026901:Membrane Transport Proteins; D017551:Microdialysis; D009419:Nerve Tissue Proteins; D009638:Norepinephrine / Q000378:metabolism*; D050484:Norepinephrine Plasma Membrane Transport Proteins; D011903:Raphe Nuclei / Q000378:metabolism*; D051381:Rats; D017208:Rats, Wistar; D012701:Serotonin / Q000378:metabolism*; D050486:Serotonin Plasma Membrane Transport Proteins; D017367:Selective Serotonin Reuptake Inhibitors / Q000494:pharmacology; D027981:Symporters
D018759:Adrenergic Uptake Inhibitors; D002352:Carrier Proteins; D015283:Citalopram; D003000:Clonidine; D003891:Desipramine; D005473:Fluoxetine; D016666:Fluvoxamine; D007099:Imipramine; D008562:Membrane Glycoproteins; D026901:Membrane Transport Proteins; D009419:Nerve Tissue Proteins; D009638:Norepinephrine; D050484:Norepinephrine Plasma Membrane Transport Proteins; D012701:Serotonin; D050486:Serotonin Plasma Membrane Transport Proteins; D017367:Selective Serotonin Reuptake Inhibitors; D027981:Symporters; C493226:Slc6a2 protein, rat; C493232:Slc6a4 protein, rat