Feedback control of upstream 5‐hydroxytryptamine (5‐HT) in the dorsal raphe nucleus (DRN) by downstream 5‐HT2A and AMPA receptors in the prefrontal cortex (PFC)

Abstract

The objective was to explore an in vivo feedback pathway that may potentially control 5‐HT in the DRN. While 5‐HT levels in the DRN have been well studied, pathways that modulate this DRN pool from downstream cascade interactions have been difficult to elucidate. This work supports at least one pathway that appears to contribute to the feedback dynamics of 5‐HT levels in the upstream DRN. Neurosurgical implantation of microdialysis two probes were placed into the DRN and PFC from which 5‐HT measurements were simultaneously recorded; DOI (5‐HT2A agonist) and NBQX (AMPA antagonist) were also delivered via these probes to the PFC and DRN, respectively. Three different regimens were tested: I) aCSF, DOI(100 μM), DOI(500 μM), DOI(800 μM); II) aCSF, DOI(100 μM); III) DOI(100 μM)+NBQX(50 μM), DOI(100 μM+NBQX(150 μM), DOI(100 μM)+NBQX(300 μM). In Regimen I, DOI, at all three concentrations, increased DRN and PFC 5‐HT levels. In Regiment II, DOI pharmacodynamics were determined as a positive control and resulted in time‐course, increased 5‐HT levels in the DRN and PFC. Regimen III showed NBQX gradually decreased DOI‐induced increased 5‐HT DRN levels. Pharmacodynamic evidence supports the possibility of a 5‐HT2A/AMPA feedback control circuit that originates in the PFC and modulates DRN 5‐HT levels. This work was supported by Formurex® and the University of the Pacific.