Reduced 5-HT1A- and GABAB receptor function in dorsal raphé neurons upon chronic fluoxetine treatment of socially stressed rats.

Autoinhibitory serotonin 1A receptors (5-HT1A) in dorsal raphe 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-HT1A 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-proteincoupled inwardly rectifying potassium (GIRK) currents as a measure of 5-HT1A- and GABA(B) receptor functionality. 5-HT1A- 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-HT1A receptor-mediated GIRK currents. Because GABA(B) receptor-induced GIRK responses were also suppressed, fluoxetine does not appear to desensitize 5-HT1A 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-HT1A receptor signaling in DRN neurons, but SSRI treatment can alleviate these behavioral symptoms while acting strongly on the 5-HT1A receptor signaling pathway.