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First published March 2002

Effect of chronic fluoxetine and WAY-100635 treatment on serotonergic neurotransmission in the frontal cortex

L. A. Dawson, H. Q. Nguyen, D. L. Smith, and L. E. SchechterView all authors and affiliations
Volume 16, Issue 2
https://doi.org/10.1177/026988110201600205

Abstract

Clinical augmentation strategies have shown that some improvement in antidepressant efficacy can be achieved by combining the β-adrenergic/serotonin (5-HT)1A/1B receptor antagonist (±)pindolol with a selective serotonin reuptake inhibitor (SSRI). This has lead to the hypothesis that a combination of a 5-HT1A receptor antagonist with an SSRI will lead to a faster onset of antidepressant action. Although there is a significant accumulation of acute preclinical data supporting this rationale, until recently, there have been no investigations examining the chronic effects of combining an SSRI with a 5-HT1A receptor antagonist. Here, we determined the chronic effects of fluoxetine (10 mg/kg o.d.), administered in combination with the selective 5-HT1A receptor antagonist WAY-100635 (1 mg/kg b.i.d.), on serotonergic neurotransmission in the frontal cortex using in-vivo microdialysis. Following chronic administration of fluoxetine ± WAY-100635, functional changes in serotonergic neurotransmission, as well as 5-HT1A autoreceptors, were assessed by administering fluoxetine or (±) 8-hydroxy-2-(di-n-propylamino)tetralin [(±) 8-OH-DPAT] 24 h after the last chronic dose. Chronic administration of WAY-100635 alone produced no detectable change in the functional status of the 5-HT1A receptor. However, fluoxetine alone produced a time-dependent adaptation in serotonergic transmission such that fluoxetine (acutely administered on day 15) was able to produce a two fold increase in extracellular 5-HT levels but the decrease in response to 8-OH-DPAT was completely attenuated. These data indicate that the fluoxetine-induced adaptation was mediated by desensitization of the 5-HT1A receptor. WAY-100635 given chronically in combination with fluoxetine blocked the SSRI-induced desensitization of the 5-HT1A receptor. Furthermore, chronic treatment with this combination produced no tolerance in terms of its ability to acutely increase forebrain 5-HT levels. These data suggest that augmentation of an SSRI by combined pharmacotherapy with a 5-HT1A antagonist would be effective upon prolonged exposure.

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Published In

Volume 16, Issue 2
Pages: 145 - 152
Article first published: March 2002
Issue published: March 2002

Keywords

  1. fluoxetine
  2. frontal cortex
  3. 5-hydroxytryptamine (5-HT, serotonin)
  4. 5-HT1A receptor
  5. microdialysis
  6. WAY-100635
  7. 8-OH-DPAT

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PubMed: 12095073

Authors

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L. A. Dawson
Neuroscience Research, Wyeth Ayerst, Princeton, NJ, USA; Neuropharmacology, Psychiatry CEDD, Glaxo Smith Kline, New Frontiers Science Park (North), Harlow, Essex CM19 5AW, UK; [email protected]
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L. E. Schechter
Neuroscience Research, Wyeth Ayerst, Princeton, NJ, USA
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