Depression is a complex mental disorder with psychological symptoms that include anhedonia, hopelessness, change of appetite and sleep, loss of energy, and deterioration of cognitive functions. The molecular basis of depression is unknown and there is great need for more effective therapies. Patients with major depression display abnormal metabolic activity and anatomy within specific brain regions, including the basal ganglia, frontal cortex, and thalamus suggesting dysfunction of cortical-striatal and cortical-limbic reward pathways. Depression remains a pervasive neuropsychiatric disorder linked to significant morbidity and mortality.
Dopaminergic projections from the midbrain to limbic regions regulate reward, motivation, and decision-making. The symptoms of anhedonia and loss of motivation suggest dysfunction in this circuitry, and depression may be treated effectively by agents that modulate dopaminergic activity. These observations support the hypothesis that dysregulation of dopaminergic neurotransmission may serve as an important cause of depression. Aberrant PKA signaling has been implicated in mental illnesses including schizophrenia, attention deficit hyperactivity disorder, obsessive-compulsive disorder, and depression. Many therapeutic agents targeting these conditions act on monoamine receptors that regulate the cAMP/PKA cascade. We are studying the regulation of the G protein-coupled receptor/adenylate kinase/cAMP/PKA/phosphodiesterase signaling and characterizing novel mechanisms that may serve as therapeutic targets for drug discovery.
See the following publication to learn more about our mood disorder research:
Kuroiwa, M., Snyder, G.L., Shuto, T., Fukuda, A., Yanagawa, Y., Bibb, J.A., Nairn, A.C., Greengard, P., and Nishi, A. (2011) A PDE4 inhibitor rolipram enhances dopamine D1 receptor/PKA/DARPP-32 signaling in cortical neurons, in press, Neuropsychopharmacology 219:1065-79.
Drerup, J.M., Hayashi, K, Cui, H., Mettlach, G.L., Long, M.A., Marvin, M., Sun, X., Goldberg, M.S., Lutter, M. Bibb, J.A. (2010) Attention-Deficit/Hyperactivity-like phenotype in mice lacking the cyclin-dependent kinase 5 cofactor p35, Jour. of Biol. Psych. 68:1163-71 Dec. 15, 2010 issue cover photo.
Kansy, J.W., Katsovich, L., McIver, K., Pick, J., Leckman, J.F., Lombroso, P.J., Zabriskie, J.B., and Bibb, J.A. (2006) Identification of pyruvate kinase as an antigen associated with Tourette syndrome. J. Nueruoimmunology181: 165-176.
Georgescu, D., Sears, R.M., Hommel, J.D., Barrot, M., Marsh, D.J., Bibb, J.A., Maratos-Flier, E., Nestler, E.J. and DiLeone, R.J. (2005) The neuropeptide MCH controls feeding behavior via a novel hypothalamic-limbic circuit. J. Neurosci.25: 2933-2940.
Nishi, A., Bibb, J.A., Higashi, H., Nairn, A.C. and Greengard, P. (2000) Amplification of dopaminergic signaling by a novel positive feedback loop. Proc. Natl. Acad. Sci. USA 97: 12840-12845.
27. Mani, S.K., Fienberg, A.A., O’Callaghan, J.P., Snyder, G.L., Allen, P.B., Mitchell, A.J., Bibb, J.A., Greengard, P., and O’Malley, B.W. (2000) The neuronal phosphoprotein DARPP-32 is required for dopamine and progesterone-facilitated sexual behavior in female rodents. Science 287:1053-6.