Reduced 5-HT_1A- and GABA_B receptor function in dorsal raphé neurons upon chronic fluoxetine treatment of socially stressed rats

Autoinhibitory serotonin 1A receptors (5-HT_1A) in dorsal raphé nucleus (DRN) have been implicated in chronic depression and in actions of selective serotonin reuptake inhibitors (SSRI). Due to experimental limitations, it was never studied at single-cell level whether changes in 5-HT_1A receptor functionality occur in depression and during SSRI treatment. Here we address this question in a social stress paradigm in rats that mimics anhedonia, a core symptom of depression. We used whole cell patch-clamp recordings of 5-HT- and baclophen-induced G-protein-coupled inwardly rectifying potassium (GIRK) currents as a measure of 5-HT_1A- and GABA_B receptor functionality. 5-HT_1A- and GABA_B receptor-mediated GIRK-currents were not affected in socially stressed rats, suggesting that there was no abnormal (auto)inhibition in the DRN on social stress. However, chronic fluoxetine treatment of socially stressed rats restored anticipatory behavior and reduced the responsiveness of 5-HT_1A receptor-mediated GIRK currents. Because GABA_B receptor-induced GIRK responses were also suppressed, fluoxetine does not appear to desensitize 5-HT_1A receptors but rather one of the downstream components shared with GABA_B receptors. This fluoxetine effect on GIRK currents was also present in healthy animals and was independent of the animal's "depressed" state. Thus our data show that symptoms of depression after social stress are not paralleled by changes in 5-HT_1A receptor signaling in DRN neurons, but SSRI treatment can alleviate these behavioral symptoms while acting strongly on the 5-HT_1A receptor signaling pathway.