Anxiety is one of the most prevalent psychiatric disorders in the U.S.A., currently affecting ~20 million individuals. The currently available anxiolytics, while somewhat effective, have side effects and target a limited number of mechanisms. Exploring novel mechanisms or strategies to treat anxiety is still an arduous task. Whereas tremendous studies indicate an important role for cholecystokinin (CCK) system in the pathogenesis of anxiety, the underlying cellular and molecular mechanisms remain unsolved. Because elevation in glutamatergic functions underlies the generation of anxiety, we have examined the effects of CCK on glutamatergic transmission in the hippocampus, a structure closely involved in the processing of context-related information and the expression of anxiety responses to environmental signals. We have substantial preliminary data demonstrating that CCK increased glutamate release at multiple synapses of the hippocampus via inhibition of the delayed rectifier K+ channels (IK). We have also shown that CCK increased NMDA type of glutamate receptor-mediated currents in isolated hippocampal neurons. The effects of CCK on glutamate release and NMDA receptor function were mediated by CCK-2 receptors and required the functions of phospholipase C (PLC) and protein kinase C (PKC). Using two animal anxiety models (Elevated plus maze and Vogel Conflict test), we demonstrated that CCK-induced increase in anxiety was mediated via ionotropic glutamate receptors. The objective of this project is to determine the involved detailed cellular and molecular mechanisms by testing the hypothesis that CCK-induced increase in glutamatergic function is responsible for its anxiogenic effects.
Specific Aim 1 will identify the detailed ionic and signaling mechanisms underlying CCK-mediated facilitation of glutamate release at multiple hippocampal synapses by recording IK from presynaptic neurons and evoked AMPA EPSCs at each synapse type of the hippocampus. We will combine pharmacological approaches and knockout mice to determine the involved intracellular signaling molecules.
Specific Aim 2 will determine the cellular and molecular mechanisms underlying CCK-mediated enhancement of NMDA currents. We will test the hypothesis that CCK enhances whole-cell NMDA currents by increasing both the membrane expression and the function of NMDA receptors. We will perform electrophysiological and immunocytochemical measurements of CCK-induced increases in membrane expression of NMDA receptors.
Specific Aim 3 will determine the cellular and molecular mechanisms of CCK in anxiety. We will test the hypothesis that the functions of PLC and PKC are involved in CCK-mediated anxiogenic effects using two animal anxiety models (Elevated plus maze and Vogel Conflict test). We believe that determination of the mechanisms underlying CCK-mediated anxiogenic effects would contribute significantly to the therapy of anxiety disorders.

Public Health Relevance

Anxiety disorders are among the most common psychiatric disorders and affect about 20 million American people. Cholecystokinin (CCK) system in the brain has long been known to underlie the pathogenesis of anxiety. However, the molecular and cellular mechanisms whereby CCK facilitates anxiety remain unsolved. Because elevation in glutamatergic functions underlies the generation of anxiety, we have examined the effects of CCK on glutamatergic functions in the hippocampus, an important limbic structure that is involved in controlling mood and emotion. We have substantial preliminary data demonstrating that CCK increases glutamate release at multiple synapses of the hippocampus. We have also shown that CCK increases NMDA type of glutamate receptor-mediated currents in isolated hippocampal neurons. Using two animal anxiety models (Elevated plus maze and Vogel Conflict test), we demonstrated that CCK-induced increase in anxiety is mediated via ionotropic glutamate receptors. The overall objective of this application is to determine the involved detailed cellular and molecular mechanisms by testing the hypothesis that CCK-induced increase in glutamatergic function is responsible for its anxiogenic effects. We believe that determination of the mechanisms underlying CCK-mediated anxiogenic effects would contribute significantly to the therapy of anxiety disorders.

Agency
National Institute of Health (NIH)
Institute
National Institute of Mental Health (NIMH)
Type
Research Project (R01)
Project #
5R01MH082881-05
Application #
8249428
Study Section
Neurotransporters, Receptors, and Calcium Signaling Study Section (NTRC)
Program Officer
Nadler, Laurie S
Project Start
2008-07-01
Project End
2013-07-31
Budget Start
2012-05-01
Budget End
2013-07-31
Support Year
5
Fiscal Year
2012
Total Cost
$300,713
Indirect Cost
$77,963
Name
University of North Dakota
Department
Pharmacology
Type
Schools of Medicine
DUNS #
102280781
City
Grand Forks
State
ND
Country
United States
Zip Code
58202
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