Modulatory effects of 5‐HT2A and AMPA receptors on in vivo serotonin levels in two key areas of the brain related to depression (1059.12)

Abstract

In this work, we explored two in vivo pharmacodynamic targets that alter serotonin (5‐HT): AMPA and 5‐HT2A receptors in the dorsal raphe nucleus (DRN) and prefrontal cortex (PFC). We hypothesized that agonism of PFC 5‐HT2A receptors would modulate DRN 5‐HT levels through DRN AMPA receptors. Two microdialysis probes were surgically placed into the DRN and PFC from which 5‐HT measurements were simultaneously recorded. DOI (5‐HT2A agonist), NBQX (AMPA antagonist) and s‐AMPA (AMPA agonist) were delivered via these probes. Three experimental protocols were tested, each with minimum of 14 time data points (n=3‐5) were obtained: A) baseline control (aCSF); DOI (100μΜ). B) aCSF; DOI (100μΜ) + NBQX (300μΜ); C) aCSF; (s)‐AMPA (10μΜ); (s)‐AMPA (50μΜ); (s)‐AMPA (85μΜ). In Protocol A, 5‐HT levels in the DRN and PFC both increased compare to controls. In Protocol B, DOI (100uM)+NBQX (300uM) showed decreased 5‐HT levels compared to a DOI infusion only (100uM). In Protocol C, as s‐AMPA concentration was increased, 5‐HT levels in DRN simultaneously increased. The results support targeting the PFC 5‐HT2A receptor or the DRN AMPA receptor directly to modulate DRN [5‐HT] for future potential anti‐depressant modalities.Grant Funding Source: Supported by Formurex, Inc.