Effects of the pharmacologic manipulation of dorsal raphe sub-regions in the modulation of defensive behaviors related to generalized anxiety and panic disorders

Abstract

A wealth of evidence indicates that the dorsal raphe nucleus (DR) is not a homogenous structure, but an aggregate of different subpopulations of serotonergic and non-serotonergic neurons that are morphologically and functionally distinct. Other findings suggest that serotonergic neurons within the dorsomedial and caudal parts of the DR are involved in anxiety processing while those within the lateral wings (lwDR) and ventrolateral periaqueductal gray (vlPAG) are responsive to panic-evoking stimuli/situations. The main goal of this research proposal is to assess the effects of the pharmacologic manipulation of 5-HT1A receptors placed within different subnuclei of the DR on inhibitory avoidance and escape responses generated by the elevated T-maze. Such effects will be analyzed after administration of different doses of the 5-HT1A receptor antagonist WAY-100635, and of the 5-HT1A receptor agonist 8-OH-DPAT into the dorsal (DRd) and caudal (DRc) subnuclei of the DR, and into the lwDR. In the second part of this project, we will employ in vivo microdyalisis to assess 5-HT levels in areas innervated by the DR, such as amygdala and dorsal periaqueductal gray, after infusion of WAY-100635 into DR sub-regions. Finally, in the third phase of this project, we will analyze the activation pattern of serotonergic neurons placed in DR projection sites using immunohistochemistry techniques for detection of the Fos protein and immunofluorescence methods for assessment of the co-localization of the Fos-protein with 5-HT1A and 5-HT2A/2C receptors after administration of WAY-100635 into DR sub-regions. (AU)