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An increase in central postsynaptic 5-hydroxytryptamine (5-HT) function activates expression of activity-related cytoskeletal protein (Arc). Here, Arc expression was used to test whether, in rats, co-administration of a 5-HT re-uptake inhibitor (paroxetine) and a 5-HT1A receptor antagonist (WAY 100635) increases postsynaptic 5-HT function. After pre-treatment with WAY 100635 (0.3 mg/kg s.c.), paroxetine (5 mg/kg s.c.) caused a threefold increase in 5-HT in prefrontal cortex microdialysates. In situ hybridization studies found that neither paroxetine (5 mg/kg s.c.) nor WAY 1000635 (0.3 mg/kg s.c.) altered Arc mRNA abundance in any region examined. In contrast, paroxetine (5 mg/kg s.c.) increased Arc mRNA after pre-treatment with WAY 100635 (0.3 mg/kg s.c.). This increase was apparent in cortical regions (frontal, parietal and cingulate) and caudate nucleus but was absent in hippocampus (CA1). Increases in Arc mRNA were accompanied by an increase in c-fos mRNA. The increase in Arc expression induced by paroxetine/WAY 100635 was abolished by the 5-HT synthesis inhibitor, p-chlorophenylalanine (300 mg/kg i.p., daily for two days). In conclusion, paroxetine and WAY 100635 injected in combination (but not alone) caused a region-specific, 5-HT-mediated increase in Arc expression. These data provide molecular evidence that co-administration of a 5-HT re-uptake inhibitor and 5-HT1A receptor antagonist increases 5-HT function at the postsynaptic level.

Type

Journal article

Journal

J Neurochem

Publication Date

06/2003

Volume

85

Pages

1480 - 1487

Keywords

Animals, Biomarkers, Cytoskeletal Proteins, Drug Synergism, Extracellular Space, Gene Expression, Male, Microdialysis, Nerve Tissue Proteins, Paroxetine, Piperazines, Prefrontal Cortex, Proto-Oncogene Proteins c-fos, Pyridines, RNA, Messenger, Rats, Rats, Sprague-Dawley, Receptors, Serotonin, Receptors, Serotonin, 5-HT1, Serotonin, Serotonin Antagonists, Serotonin Uptake Inhibitors, Synapses