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.

Agency
National Institute of Health (NIH)
Institute
National Institute of Mental Health (NIMH)
Type
Predoctoral Individual National Research Service Award (F31)
Project #
5F31MH012091-03
Application #
6185123
Study Section
Neuropharmacology and Neurochemistry Review Committee (NPNC)
Program Officer
Goldschmidts, Walter L
Project Start
2000-07-01
Project End
Budget Start
2000-07-10
Budget End
2001-06-30
Support Year
3
Fiscal Year
2000
Total Cost
$21,460
Indirect Cost
Name
University of Virginia
Department
Pharmacology
Type
Schools of Medicine
DUNS #
001910777
City
Charlottesville
State
VA
Country
United States
Zip Code
22904
Talley, Edmund M; Sirois, Jay E; Lei, Qiubo et al. (2003) Two-pore-Domain (KCNK) potassium channels: dynamic roles in neuronal function. Neuroscientist 9:46-56
Washburn, Christopher P; Sirois, Jay E; Talley, Edmund M et al. (2002) Serotonergic raphe neurons express TASK channel transcripts and a TASK-like pH- and halothane-sensitive K+ conductance. J Neurosci 22:1256-65
Bayliss, D A; Talley, E M; Sirois, J E et al. (2001) TASK-1 is a highly modulated pH-sensitive 'leak' K(+) channel expressed in brainstem respiratory neurons. Respir Physiol 129:159-74
Talley, E M; Solorzano, G; Lei, Q et al. (2001) Cns distribution of members of the two-pore-domain (KCNK) potassium channel family. J Neurosci 21:7491-505
Lei, Q; Talley, E M; Bayliss, D A (2001) Receptor-mediated inhibition of G protein-coupled inwardly rectifying potassium channels involves G(alpha)q family subunits, phospholipase C, and a readily diffusible messenger. J Biol Chem 276:16720-30
Talley, E M; Bayliss, D A (2000) Postnatal development of 5-HT(1A) receptor expression in rat somatic motoneurons. Brain Res Dev Brain Res 122:10-Jan
Sirois, J E; Lei, Q; Talley, E M et al. (2000) The TASK-1 two-pore domain K+ channel is a molecular substrate for neuronal effects of inhalation anesthetics. J Neurosci 20:6347-54
Talley, E M; Lei, Q; Sirois, J E et al. (2000) TASK-1, a two-pore domain K+ channel, is modulated by multiple neurotransmitters in motoneurons. Neuron 25:399-410
Talley, E M; Solorzano, G; Depaulis, A et al. (2000) Low-voltage-activated calcium channel subunit expression in a genetic model of absence epilepsy in the rat. Brain Res Mol Brain Res 75:159-65
Talley, E M; Cribbs, L L; Lee, J H et al. (1999) Differential distribution of three members of a gene family encoding low voltage-activated (T-type) calcium channels. J Neurosci 19:1895-911