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.
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.