Corticosterone-induced Hippocampal 5-HT Responses were Muted in Depressive-like State

Interactions between the hypothalamic-pituitary-adrenal axis and the central 5-HT system in the depressive state remain largely unknown. The present study investigated corticosterone (CORT) regulations of extracellular 5-HT in the hippocampal CA3 in a mouse model of depression. Basal dialysate 5-HT, true extracellular 5-HT, 5-HT reuptake efficiency, and time courses of dialysate 5-HT following CORT injections at 10, 20, and 40 mg/kg were determined at baseline, depressive-like state and after subsequent fluoxetine (FLX) treatment using in vivo microdialysis in male C57BL/6 mice. Behavioral tests were used to determine behavioral phenotypes and therapeutic responses to FLX. Depressed mice showed decreased extracellular 5-HT, increased 5-HT reuptake efficiency, and absence of the increase in dialysate 5-HT response to CORT injections, which were all reversed in FLX-responsive mice. Surprisingly, the FLX nonresponsive mice continued to worsen behaviorally and exhibited lower extracellular 5-HT and higher 5-HT reuptake efficiency. Our study indicates that abolished-CORT induced 5-HT response, decreased extracellular 5-HT, and increased 5-HT reuptake efficiency might be the signature features associated with depressive-like state. Increased 5-HT reuptake efficiency was one of the underlying mechanisms, with target effectors remaining to be explored. The findings in the FLX nonresponsive mice suggest distinct neuromechanisms, which might be genetically predetermined.