Title

EXPLORING THE BEHAVIOR OF 5-HT2A AND AMPA RECEPTORS IN MODULATING SEROTONIN (5-HT) CONCENTRATIONS IN THE DORSAL RAPHE NUCLEUS (DRN)

Lead Author Affiliation

Department of Pharmaceutics and Medicinal Chemistry

Second Author Affiliation

Department of Pharmaceutics and Medicinal Chemistry

Introduction

Depression is a common mood disorders. Most research in the field of depression has focused on PFC and DRN, which have shown structural and functional abnormalities in depression.

Purpose

To explore an in-vivo feedback pathway that may contribute to the control of serotonin levels (5-hydroxytryptamine; 5-HT) in the DRN. While 5-HT levels in the DRN have been well studied, pathways that modulate this DRN pool through downstream cascade interactions leading to an upstream feedback loop have been difficult to elucidate.

Method

Male Wistar rats underwent neurosurgery for implantation of microdialysis (MD) probes (DRN: Lateral angle of 30°, AP: 0.78mm; ML: 0.31mm; DV: 0.75mm; PFC coordinates: AP: 0.32mm; ML: 0.10mm; DV: 0.60mm). Three to five rats were randomly assigned to one of four experimental arms, Regimen I, II, III or IV. DOI (5-HT2A agonist) and NBQX (AMPA antagonist) were also delivered via these probes to the PFC and DRN, respectively. Four different regimens were tested: I) aCSF, DOI (100), DOI (500), DOI (800); II) aCSF, DOI (100); III) DOI (100) + NBQX (50), DOI (100+ NBQX (150), DOI (100) + NBQX (300); IV) aCSF, DOI (100) + NBQX (300). Appropriate controls were performed. Perfusion of artificial cerebrospinal fluid (aCSF) though MD was performed for 1 to 2 hours to establish baseline serotonin levels. Drugs were infused directly into the DRN and PFC and 30 μL fractions were collected every 20minutes (flow rate = 1.5μL/min) for six hours.

Results

In the presence of all three concentrations of DOI (Regimen I), 5-HT levels in DRN and PFC both increased compare to control. In Regimen II, DOI pharmacodynamics were determined as a positive control and resulted in time-course, increased 5-HT levels in the DRN and PFC. In Regimen III, different concentrations of NBQX were added to block the effect of AMPA receptor. It gradually decreased DOI-induced increased 5-HT DRN levels. In Regiment IV, the effects on 5-HT levels of adding NBQX would decrease DOI-induced increased 5-HT DRN level during a longer infusion time.

Significance

The result supports the possibility of a 5-HT2A/AMPA feedback control circuit that originates in the PFC and modulates DRN 5-HT levels through feedback coupling of 5-HT. A more complete characterization of relationship between the PFC and DRN would help clarify the interactions between these two key areas and improve our understanding of the action of 5-HT receptors. This may open new approaches to the treatment of depression, with the possibility to address multiple receptors and /or neurotransmitters.

Location

DeRosa University Center, Stockton campus, University of the Pacific

Format

Poster Presentation

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Mar 25th, 10:00 AM Mar 25th, 3:00 PM

EXPLORING THE BEHAVIOR OF 5-HT2A AND AMPA RECEPTORS IN MODULATING SEROTONIN (5-HT) CONCENTRATIONS IN THE DORSAL RAPHE NUCLEUS (DRN)

DeRosa University Center, Stockton campus, University of the Pacific

Depression is a common mood disorders. Most research in the field of depression has focused on PFC and DRN, which have shown structural and functional abnormalities in depression.