A single link to the first track to allow the export script to build the search page
  • Addiction, Drugs
  • Information from Lay-Language Summaries is Embargoed Until the Conclusion of the Scientific Presentation

    857—Prefrontal and Striatal Systems: Molecular Mechanisms

    Wednesday, November 13, 2013, 1:00 pm - 5:00 pm

    857.09: Regulation of cAMP signaling in ventral striatum via phosphodiesterase-4 (PDE4) and cyclin-dependent kinase (Cdk5) controls mood and acts as a target for the development of antidepressants

    Location: Halls B-H

    *F. PLATTNER1, K. HAYASHI2, D. R. BENAVIDES3, A. HERNANDEZ4, T. C. TASSIN1, C. TAN1, J. DAY5, M. W. FINA1, A. C. NAIRN6, P. GREENGARD7, E. J. NESTLER8, A. NISHI9, R. TAUSSIG1, M. D. HOUSLAY10, J. A. BIBB1;
    1Dept. of Psychiatry, UT Southwestern Med. Ctr., Dallas, TX; 2Sch. of Med., Keio Univ., Tokyo 160-8582, Japan; 3Dept. of Neurol., The Johns Hopkins Univ. Sch. of Med., Baltimore, MD; 4Psychiatry, The Univ. of Texas Southwestern Med. Ctr., Dallas, TX; 5Div. of Neurosci. and Mol. Pharmacol., Univ. of Glasgow, Glasgow, United Kingdom; 6Psychiatry, Yale Univ., New Haven, CT; 7Lab. of Mol. and Cell. Neurosci., The Rockefeller Univ., New York, NY; 8Dept. of Neurosci., Mount Sinai Sch. of Med., New York, NY; 9Pharmacol., Kurume Univ. Sch. of Med., Kurume, Japan; 10Pharmaceut. Sci., King's Col. London, London, United Kingdom

    Abstract Body: Current antidepressant medications have limited efficacy and long therapeutic delays. Therefore, a better understanding of the molecular mechanisms underlying the pathophysiology of depression is needed to identify new targets and develop more effective and rapidly-acting treatments. Here, we report that cyclin-dependent protein kinase 5 (Cdk5) controls cAMP degradation in ventral striatum via activation of phosphodiesterase-4 (PDE4) and implicate this novel molecular mechanism in depression-like behavior. Phosphorylation of PDE4 by Cdk5 contributes to its activation thereby controlling cAMP signaling. Consequently, loss of Cdk5 in mouse striatal neurons disrupted this regulatory mechanism and caused elevated cAMP levels, increased cAMP-dependent protein kinase (PKA) activity, and antidepressant-like behavior. Finally, small interfering peptides that selectively target this mechanism acted as antidepressants when infused into ventral striatum. Our results demonstrate that cAMP signaling in medium spiny neurons of ventral striatum controls mood and suggest that disruption of Cdk5/PKA-dependent PDE4 activation may provide an effective treatment strategy for depression and related psychiatric disorders.

    Lay Language Summary: Our analysis of mice that are more active and resilient to stressful situations, led to the development of a small molecule with antidepressant-like properties. This molecule evoked in mice the same behavioral effects as commonly prescribed antidepressant medication, though by acting on an alternative, new target.
    Depression is one of the most common mental disorders and leading cause of disability in the developed world. The most widely administered antidepressants target the so-called monoamine systems. However, these monoamine-based therapies may take weeks to months to work and are unfortunately often accompanied by adverse side effects. Moreover, these therapies are ineffective in 20 to 40 percent of people with depression, highlighting the need for new treatment targets and approaches.
    To identify new treatment targets, we studied mice that are lacking the enzyme - known as Cdk5 - and these mice acted, as if they had been given antidepressants. We discovered that loss of Cdk5 caused an increase in the signaling molecule ‘cyclic adenosine monophosphate’ (cyclic AMP) in brain cells of the reward center.
    Normally, cyclic AMP is broken down by an enzyme called PDE4. However, in the mice that lacked Cdk5, PDE4 did not work properly, leading to a build-up of cyclic AMP and antidepressant-like behavior. Support for this observation comes from the finding that drugs, which reduce the action of cyclic AMP, prevented the antidepressant-like behavior.
    These results indicate that Cdk5 critically regulates PDE4 and thereby affects depressive behavior. Based on this new knowledge, we developed a small molecule that disrupts the regulation of PDE4 by Cdk5. When directly administered into the reward center of the brain, this small molecule evoked the same behavior as in mice treated with antidepressants.
    Our research identifies a new target, other than the monoamine system, for the treatment of depression and pinpoints the brain’s reward center as the location where this mechanism is critically functioning. The small molecule constitutes the basis for the development of novel, more effective therapies to combat depression and related disorders.
    This research was supported by the National Institute of Mental Health, the National Institute on Drug Addiction and the Dallas Depression Center at UT Southwestern Medical Center