SSRIs are an important class of antidepressants that are believed to produce their therapeutic effects by enhancing serotonergic transmission. The fact that there is a two-to-four week delay in their efficacy suggests that their benefits depend on long-term adaptive changes in the central nervous system. One of the long term effects that are thought to be crucial to SSRI treatment is the downregulation of an autoinhibitory mechanism mediated by 5-HT1A receptors on 5-HT-synthesizing raphe neurons. The autoinhibitory mechanism is well described, involving direct coupling between the 5-HT1A receptor, a heterotrimeric G-protein, and a G-protein-coupled inwardly-rectifying potassium (GIRK) channel. However, in spite of the attention it has received, the specific cellular and molecular events responsible for the SSRI-induced down-regulation of this autoinhibition remain obscure. The proposed research will use ligand binding autoradiography and whole-cell voltage clamp recordings in an in vitro slice preparation to determine the locus of regulation of this mechanism. In addition, in situ hybridization will be used to determine whether the observed down-regulation results from SSRI-induced alterations in expression of genes coding for the proteins constituent to this transduction pathway.
Specific Aims : 1) Determine effects of chronic SSRI treatment on 5HT1A receptor-G protein coupling in dorsal raphe neurons; 2) Determine effects of chronic SSRI treatment on G protein-GIRK channel coupling in dorsal raphe neurons; 3) Determine effects of chronic SSRI treatment on 5HT1A receptor and GIRK channel mRNA levels in dorsal raphe neurons.
