Upregulation of the dorsal raphe nucleus-prefrontal cortex serotonin system by chronic treatment with escitalopram in hyposerotonergic Wistar-Kyoto rats

• Published in: Neuropharmacology Vol. 72; pp. 169 - 178
• Main Authors: Yamada, Makiko, Kawahara, Yukie, Kaneko, Fumi, Kishikawa, Yuki, Sotogaku, Naoki, Poppinga, Wilfred J., Folgering, Joost H.A., Dremencov, Eliyahu, Kawahara, Hiroshi, Nishi, Akinori
• Format: Journal Article
• Language: English
• Published: England Elsevier Ltd 01-09-2013
• Subjects: Animal model; Animals; Anxiety - drug therapy; Anxiety - pathology; Citalopram - pharmacology; Depression; Disease Models, Animal; Exploratory Behavior - drug effects; Feeding Behavior - drug effects; Food Preferences - drug effects; Immobility Response, Tonic - drug effects; Male; Microdialysis; Motor Activity - drug effects; Neural Pathways - drug effects; Neural Pathways - metabolism; Prefrontal Cortex - drug effects; Prefrontal Cortex - metabolism; Raphe Nuclei - drug effects; Raphe Nuclei - metabolism; Rats; Rats, Inbred WKY; Rats, Wistar; Serotonin - metabolism; Serotonin Uptake Inhibitors - pharmacology; SSRIs; Sucrose - administration & dosage; Swimming - psychology; Up-Regulation - drug effects; Animal model; Depression; Microdialysis; SSRIs
• ISSN: 0028-3908; 1873-7064
• DOI: 10.1016/j.neuropharm.2013.04.044

Wistar-Kyoto (WKY) rats are sensitive to chronic stressors and exhibit depression-like behavior. Dorsal raphe nucleus (DRN) serotonin (5-HT) neurons projecting to the prefrontal cortex (PFC) comprise the important neurocircuitry underlying the pathophysiology of depression. To evaluate the DRN-PFC 5-HT system in WKY rats, we examined the effects of escitalopram (ESCIT) on the extracellular 5-HT level in comparison with Wistar rats using dual-probe microdialysis. The basal levels of 5-HT in the DRN, but not in the PFC, in WKY rats was reduced as low as 30% of Wistar rats. Responses of 5-HT in the DRN and PFC to ESCIT administered systemically and locally were attenuated in WKY rats. Feedback inhibition of DRN 5-HT release induced by ESCIT into the PFC was also attenuated in WKY rats. Chronic ESCIT induced upregulation of the DRN-PFC 5-HT system in WKY rats, with increases in basal 5-HT in the DRN, responsiveness to ESCIT in the DRN and PFC, and feedback inhibition, whereas downregulation of these effects was induced in Wistar rats. Thus, the WKY rat is an animal model of depression with low activity of the DRN-PFC 5HT system. The finding that chronic ESCIT upregulates the 5-HT system in hyposerotonergic WKY rats may contribute to improved understanding of mechanisms of action of antidepressants, especially in depression with 5-HT deficiency.
•WKY rats are a model of depression with low activity of the DRN-PFC 5-HT system.•Responses of 5-HT system to escitalopram challenge are attenuated in WKY rats.•Chronic escitalopram upregulates 5-HT system and its responsiveness in WKY rats.•In contrast, chronic escitalopram downregulates 5-HT system in control Wistar rats.