Suicide has a devastating impact on victims, their extended families, and public health in the United States, as well as throughout the world. Few treatments have been shown to reduce risk. An exception, supported by extensive clinical evidence, is that lithium is effective in reducing the risk of both attempted and completed suicide. However, the mechanisms underlying lithium's antisuicidal actions are not yet known, limiting the development of improved prevention approaches. We intend to use the mouse as a model organism to elucidate molecular pathways by which lithium interacts with biological and behavioral factors associated with suicide in humans. However, rather than attempting the infeasible task of modeling suicide in mice, we will focus on approaches that assess mouse behavior in tests relevant to well validated endophenotypes (deconstructed components of complex behavioral phenotypes) associated with suicide including aggression and impulsivity. These endophenotypes will be used in combination with human genetic, biochemical, and pharmacological findings in suicide research to provide construct-valid animal models. Toward this end, clinical studies have implicated polymorphisms in a number of genes, including neuronal nitric oxide synthase (NOS1), with measures of impulsivity, aggression, and suicide. Similarly, the results of extensive research have implicated deficits in serotonin (5-HT) neurotransmission in the etiology of suicidal behavior as well as increased impulsivity and aggression. Data from preclinical and human genetic studies indicate that lithium may exert some of its mood stabilizing effects through inhibition of the enzyme glycogen synthase kinase-3! (GSK-3!). Intriguingly, emerging basic science evidence links NOS1 function, 5-HT neurotransmission, and GSK-3! activity suggesting that they may be causally linked in the pathophysiological processes relevant to the etiology and treatment of psychiatric diseases such as suicide, where impulsivity and aggression play a role. Thus, our Specific Aims are to: 1) Identify the effects of lithium on behavior in mice with genetically- and pharmacologically-induced decreases in 5-HT levels;2) Identify the effects of lithium on behavior in mice with genetically- and pharmacologically-mediated deficiencies in nitric oxide synthase 1 (NOS1) activity;3) Evaluate the role of glycogen synthase kinase-3!, a direct target of lithium, in modifying behaviors mediated by decreased 5-HT and NOS1 function. These studies will capitalize on current knowledge of lithium pharmacology and use mouse genetic knockouts and pharmacological approaches to dissect the molecular and neurobiological mechanisms whereby lithium may modify impulsive and aggressive behavior as well identify points of interaction between lithium and biological markers known to be associated with suicide. Public Health Relevance: The data derived rom these studies should promote the development of improved pharmacological interventions to modify aggressive and impulsive behaviors thereby decreasing the risk of suicide across all diagnostic categories.

Public Health Relevance

A completed suicide has a devastating impact on families, society, and public health. Few treatments have been shown to result in reduced risk;however, lithium treatment is effective, for unknown reasons, in reducing the risk of both attempted and completed suicide. This application proposes experiments in the context of endophenotype strategies that will reveal molecular mechanisms whereby lithium acts to exert its therapeutics effects.

Agency
National Institute of Health (NIH)
Institute
National Institute of Mental Health (NIMH)
Type
Research Project (R01)
Project #
5R01MH091816-04
Application #
8452200
Study Section
Special Emphasis Panel (ZMH1-ERB-L (04))
Program Officer
Winsky, Lois M
Project Start
2010-07-05
Project End
2014-12-31
Budget Start
2013-01-01
Budget End
2013-12-31
Support Year
4
Fiscal Year
2013
Total Cost
$357,350
Indirect Cost
$106,920
Name
University of Maryland Baltimore
Department
Psychiatry
Type
Schools of Medicine
DUNS #
188435911
City
Baltimore
State
MD
Country
United States
Zip Code
21201
Pezzato, Fernanda A; Can, Adem; Hoshino, Katsumasa et al. (2015) Effect of lithium on behavioral disinhibition induced by electrolytic lesion of the median raphe nucleus. Psychopharmacology (Berl) 232:1441-50
Can, Adem; Schulze, Thomas G; Gould, Todd D (2014) Molecular actions and clinical pharmacogenetics of lithium therapy. Pharmacol Biochem Behav 123:3-16
Can, Adem; Piantadosi, Sean C; Gould, Todd D (2013) Differential antidepressant-like response to lithium treatment between mouse strains: effects of sex, maternal care, and mixed genetic background. Psychopharmacology (Berl) 228:411-8
Halcomb, Meredith E; Gould, Todd D; Grahame, Nicholas J (2013) Lithium, but not valproate, reduces impulsive choice in the delay-discounting task in mice. Neuropsychopharmacology 38:1937-44
Can, Adem; Dao, David T; Terrillion, Chantelle E et al. (2012) The tail suspension test. J Vis Exp :e3769
Can, Adem; Dao, David T; Arad, Michal et al. (2012) The mouse forced swim test. J Vis Exp :e3638
Courtet, P; Gottesman, I I; Jollant, F et al. (2011) The neuroscience of suicidal behaviors: what can we expect from endophenotype strategies? Transl Psychiatry 1: