Galanin, a broadly expressed neuropeptide, when applied intracerebroventricularly impairs cognitive performance, dampens seizure activity, and affects sexual activity and feeding behaviors. These diverse pharmacological effects are exerted by at least three known G protein coupled receptors: GALR1, GALR2, and GALR3. The in vivo effects of galanin have been determined by using the peptide galanin and some high affinity chimeric galanin antagonists, M15, M35 and M40, which we introduced. These ligands lack receptor subtype selectivity, and thus the contribution of the specific galanin receptor subtypes to the multiple in vivo effects of galanin is not known. The second messenger systems coupled to activation of the different galanin receptor subtypes have been studied in transfected non-neuronal cells, leaving in doubt whether the same signaling occurs in hippocampal neurons expressing these receptors with their own set of G-proteins. In this study we wish to determine the contribution of GALR1, expressed in pyramidal cells of CA1, and of GALR2, expressed in the granule cells in the dentate gyrus, to signaling in these neurons. We will examine CREB and MAPK pathways and hippocampal excitability, including LTP in the dentate gyrus and CA1 regions, which are markedly depressed by galanin. In the absence of receptor subtype-specific ligands, to determine the roles of specific galanin receptor subtypes we will utilize the GALR1 (-/-) transgenic mice and in vivo down regulation of GALR1 and GALR2 expression by cell penetrating peptide nucleic acid (PNA) type antisense oligonucleotides applied icv. Finally, the subtype(s) specificity of presynaptic galanin receptors that regulate noradrenaline (NE), glutamate and acetylcholine (ACh) release in the hippocampus will be addressed in microdialysis experiments. We hypothesize that galanin acting at GALR1 and GALR2 receptors suppresses hippocampal excitability with consequences for seizure threshold and cognitive function. It is expected that the results will form the basis for understanding the role of different galanin receptor subtypes in cognition, and define these galanin receptor subtypes as putative drug targets for cognitive performance-enhancing drugs. Furthermore, these galanin receptor subtypes participate in the regulation of the firing of serotonergic and noradrenergic cells in the brain, and information regarding their mechanism of action in the hippocampus may contribute to understanding their effects in these monoaminergic systems, and in depression. Also, because galanin has been shown to have anti-epileptic actions, understanding how this peptide regulates seizures could have clinical applications in the treatment of epilepsy.

Agency
National Institute of Health (NIH)
Institute
National Institute of Mental Health (NIMH)
Type
Research Project (R01)
Project #
5R01MH063080-03
Application #
6723694
Study Section
Integrative, Functional and Cognitive Neuroscience 8 (IFCN)
Program Officer
Winsky, Lois M
Project Start
2002-03-01
Project End
2007-02-28
Budget Start
2004-03-05
Budget End
2005-02-28
Support Year
3
Fiscal Year
2004
Total Cost
$416,700
Indirect Cost
Name
Scripps Research Institute
Department
Type
DUNS #
781613492
City
La Jolla
State
CA
Country
United States
Zip Code
92037
Mitsukawa, K; Lu, X; Bartfai, T (2010) Galanin, galanin receptors, and drug targets. EXS 102:7-23
Lu, Xiaoying; Bartfai, Tamas (2009) Analyzing the validity of GalR1 and GalR2 antibodies using knockout mice. Naunyn Schmiedebergs Arch Pharmacol 379:417-20
Mitsukawa, K; Lu, X; Bartfai, T (2009) Bidirectional regulation of stress responses by galanin in mice: involvement of galanin receptor subtype 1. Neuroscience 160:837-46
Lu, Xiaoying; Ross, Brendon; Sanchez-Alavez, Manuel et al. (2008) Phenotypic analysis of GalR2 knockout mice in anxiety- and depression-related behavioral tests. Neuropeptides 42:387-97
Mitsukawa, K; Lu, X; Bartfai, T (2008) Galanin, galanin receptors and drug targets. Cell Mol Life Sci 65:1796-805
Lu, Xiaoying; Sharkey, Lisa; Bartfai, Tamas (2007) The brain galanin receptors: targets for novel antidepressant drugs. CNS Neurol Disord Drug Targets 6:183-92
Zorrilla, E P; Brennan, M; Sabino, V et al. (2007) Galanin type 1 receptor knockout mice show altered responses to high-fat diet and glucose challenge. Physiol Behav 91:479-85
Robinson, J K; Bartfai, T; Langel, U (2006) Galanin/GALP receptors and CNS homeostatic processes. CNS Neurol Disord Drug Targets 5:327-34
Shi, Tie-Jun Sten; Hua, Xiao-Ying; Lu, Xiaoying et al. (2006) Sensory neuronal phenotype in galanin receptor 2 knockout mice: focus on dorsal root ganglion neurone development and pain behaviour. Eur J Neurosci 23:627-36
Kovacs, Z; Kekesi, K A; Szilagyi, N et al. (2006) Facilitation of spike-wave discharge activity by lipopolysaccharides in Wistar Albino Glaxo/Rijswijk rats. Neuroscience 140:731-42

Showing the most recent 10 out of 20 publications