title: In vivo effects of the simultaneous blockade of serotonin and norepinephrine transporters on serotonergic function. Microdialysis studies.
abstract: 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.
authors.affiliation: Department of Neurochemistry, Consejo Superior de Investigaciones Cientificas, Barcelona, Spain.
authors.forename: N
authors.initials: N
authors.lastname: Bel
authors.forename: F
authors.initials: F
authors.lastname: Artigas
mesh_terms: 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
chemical_list: 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