Abstract

In humans, positive affective states are associated with resilience to depression as well as increased global health and decreased mortality. Currently available antidepressants fail to treat the symptom of decreased positive affect associated with depression. Targeting positive affective states associated with resilience to depression is an attractive alternative treatment approach. Rat hedonic 50-kHz ultrasonic vocalizations (hedonic USVs) are a well established measure of positive affective states. Using this model, we have identified Insulin-like Growth Factor-I as functionally involved in positive- affect-induced resilience to depression. In humans, Insulin-like Growth Factor I (IGFI) has been shown to both increase positive affect and reduce symptoms of depression and anxiety, but peripheral side effects (hypoglycemia) limits its clinical utility. The proposed studies will furthr examine the functional role of IGFI resilience to depression. In these proposed experiments, (i) the optimal brain region for IGFI-induced positive affect and antidepressant effects will be determined, (ii) IGFI-induced resilience will be examined using multiple animal measure of positive affect and depression, and (iii) the therapeutic potential of Insulin-like growth factor binding protein 2 (IGFBP-2) as a treatment for depression will be determined. Studying positive affect and how it relates to resilience to depression is a unique approach that may lead to the creation of novel antidepressants.

Public Health Relevance

Depression affects over 10% of the adult population and is projected to become the second leading cause of death by 2020. Less than 30% of depressed patients respond to currently available antidepressants which work primarily by decreasing negative emotions. In this application, the mechanism of IGFI-induced positive affect and resilience to depression will be studied with the goal of providing mechanistic insight, as well as creating a novel therapeutic development pathway, for the treatment of depression.

  Funding Agency

Agency
National Institute of Health (NIH)
Institute
National Institute of Mental Health (NIMH)
Type
Research Project (R01)
Project #
5R01MH094835-03
Application #
8609073
Study Section
Neurobiology of Motivated Behavior Study Section (NMB)
Program Officer
Meinecke, Douglas L
Project Start
2012-04-06
Project End
2017-01-31
Budget Start
2014-02-01
Budget End
2015-01-31
Support Year
3
Fiscal Year
2014
Total Cost
Indirect Cost

  Institution

Name
Northwestern University at Chicago
Department
Biomedical Engineering
Type
Biomed Engr/Col Engr/Engr Sta
DUNS #
City
Evanston
State
IL
Country
United States
Zip Code
60201

  Publications

Burgdorf, Jeffrey; Colechio, Elizabeth M; Ghoreishi-Haack, Nayereh et al. (2017) IGFBP2 Produces Rapid-Acting and Long-Lasting Effects in Rat Models of Posttraumatic Stress Disorder via a Novel Mechanism Associated with Structural Plasticity. Int J Neuropsychopharmacol 20:476-484
Burgdorf, Jeffrey; Colechio, Elizabeth M; Stanton, Patric et al. (2017) Positive Emotional Learning Induces Resilience to Depression: A Role for NMDA Receptor-mediated Synaptic Plasticity. Curr Neuropharmacol 15:3-10
Moskal, Joseph R; Burgdorf, Jeffrey S; Stanton, Patric K et al. (2017) The Development of Rapastinel (Formerly GLYX-13); A Rapid Acting and Long Lasting Antidepressant. Curr Neuropharmacol 15:47-56
Rajagopal, Lakshmi; Burgdorf, Jeffrey S; Moskal, Joseph R et al. (2016) GLYX-13 (rapastinel) ameliorates subchronic phencyclidine- and ketamine-induced declarative memory deficits in mice. Behav Brain Res 299:105-10
Burgdorf, Jeffrey; Kroes, Roger A; Zhang, Xiao-lei et al. (2015) Rapastinel (GLYX-13) has therapeutic potential for the treatment of post-traumatic stress disorder: Characterization of a NMDA receptor-mediated metaplasticity process in the medial prefrontal cortex of rats. Behav Brain Res 294:177-85
Burgdorf, J; Zhang, X-L; Weiss, C et al. (2015) The long-lasting antidepressant effects of rapastinel (GLYX-13) are associated with a metaplasticity process in the medial prefrontal cortex and hippocampus. Neuroscience 308:202-11
Burgdorf, Jeffrey; Zhang, Xiao-lei; Colechio, Elizabeth M et al. (2015) Insulin-Like Growth Factor I Produces an Antidepressant-Like Effect and Elicits N-Methyl-D-Aspartate Receptor Independent Long-Term Potentiation of Synaptic Transmission in Medial Prefrontal Cortex and Hippocampus. Int J Neuropsychopharmacol 19:
Moskal, Joseph R; Burch, Ronald; Burgdorf, Jeffrey S et al. (2014) GLYX-13, an NMDA receptor glycine site functional partial agonist enhances cognition and produces antidepressant effects without the psychotomimetic side effects of NMDA receptor antagonists. Expert Opin Investig Drugs 23:243-54
Burgdorf, Jeffrey; Moskal, Joseph R; Brudzynski, Stefan M et al. (2013) Rats selectively bred for low levels of play-induced 50 kHz vocalizations as a model for autism spectrum disorders: a role for NMDA receptors. Behav Brain Res 251:18-24
Burgdorf, Jeffrey; Zhang, Xiao-lei; Nicholson, Katherine L et al. (2013) GLYX-13, a NMDA receptor glycine-site functional partial agonist, induces antidepressant-like effects without ketamine-like side effects. Neuropsychopharmacology 38:729-42

Showing the most recent 10 out of 12 publications