Nucleus accumbens cross-section (top) and 3D whole-brain reconstruction (bottom) showing the brain circuitry (in green) where cyclic AMP signaling was increased by turning off Cdk5-phosphodiesterase regulation to achieve anti-depressant effects.Image derived by F. Plattner, A. Hernandez, G. Mettlach, and J. Bibb, UT Southwestern Psychiatry Department; D.Ramirez and J. Meeks, Whole Brain Imaging Facility of the Texas Institute for Brain Injury and Repair at UT Southwestern; and J.Schwartz and T. Regan, TissueVision, Inc.The study, which appears in Nature Neuroscience, determined that elevating levels of the molecule cyclic adenosine monophosphate (cAMP) in brain cells had a positive impact on stress-induced behaviors in mice. Other studies have shown that patients with major depressive disorder often have impaired cAMP signaling and that chronic antidepressant treatments often turn on this signaling system.

“This is the first step in the development of a treatment for patients with major depressive disorder using this new strategy,” said senior author Dr. James Bibb, Professor of Psychiatry, and Neurology and Neurotherapeutics at UT Southwestern.

Major depressive disorder (MDD) may be triggered or exacerbated by severe or chronic stress. Depression affects more than 120 million people worldwide. Between 20 percent to 40 percent of people with depression are not helped by existing therapies, highlighting the need for new treatments and approaches.

The study was supported by the Center for Depression Research and Clinical Care at UT Southwestern. The Center, established with a $5 million lead gift from the Hersh Foundation earlier this year, combines basic research, translational clinical research in genetics, functional brain imaging, and treatment research across the entire age span, with a special focus on treatment of resistant, chronic, or recurrent depression.

Dr. James BibbPhoto courtesy of the UT Southwestern Medical Center“These exciting findings could help us develop very novel treatments to reduce stress response and prevent or treat depression effectively in the future,” said Dr. Madhukar Trivedi, Director of the Center for Depression Research and Clinical Care, Chief of the Division of Mood Disorders, Professor of Psychiatry, and holder of the Betty Jo Hay Distinguished Chair in Mental Health.

The chemical changes occurred in a region of the brain called the nucleus accumbens, which has a significant role in the processing of motivation, pleasure, and reward.

Researchers found that levels of cAMP can be elevated by disrupting the activation of an enzyme called phosphodiesterase-4 (PDE4). Knocking out the regulatory protein kinase Cdk5 in brain cells disrupted PDE4 function and elevated cAMP levels. This positively affected behavioral responses of the mice to stress-inducing experiments.

The researchers then developed a drug-like peptide that selectively blocked PDE4 function and increased the struggling response of mice to a test of acute stress commonly used to assess antidepressant efficacy.

Other UT Southwestern researchers who contributed to this study were lead author Dr. Florian Plattner, Instructor of Psychiatry; Dr. Ron Taussig, Associate Professor of Pharmacology; Adan Hernandez, senior research associate in Psychiatry; and Chungfeng Tan, research associate in Psychiatry.

This work was supported by the National Institutes of Health, the Brain and Behavior Research Foundation, National Research Service Award from the National Institute on Drug Abuse, and the California Metabolic Research Foundation.