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

Neuroscience Research, Wyeth Ayerst, Princeton, NJ, USA; Neuropharmacology, Psychiatry CEDD, Glaxo Smith Kline, New Frontiers Science Park (North), Harlow, Essex CM19 5AW, UK; lee_a_dawson{at}gsk.com

H. Q. Nguyen

D. L. Smith

L. E. Schechter

Neuroscience Research, Wyeth Ayerst, Princeton, NJ, USA

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-HT_1A 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-HT_1A receptor antagonist. Here, we determined the chronic effects of fluoxetine (10 mg/kg o.d.), administered in combination with the selective 5-HT_1A 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-HT_1A 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-HT_1A 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-HT_1A receptor. WAY-100635 given chronically in combination with fluoxetine blocked the SSRI-induced desensitization of the 5-HT_1A 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-HT_1A antagonist would be effective upon prolonged exposure.

Key Words: fluoxetine • frontal cortex • 5-hydroxytryptamine (5-HT, serotonin) • 5-HT1A receptor • microdialysis • WAY-100635 • 8-OH-DPAT

Journal of Psychopharmacology, Vol. 16, No. 2, 145-152 (2002)
DOI: 10.1177/026988110201600205


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