Drug Addiction Research
Drug Addiction is a severe neuropsychiatric disorder characterized by loss of control over motivated behavior. The role of synaptic plasticity in addiction has become clearer, while the underlying molecular mechanisms contributing to the formation of the addicted state are being delineated. We want to better understand the role of striatal signal transduction in addiction from a more integrative neurobiological perspective. Drugs of abuse alter dopaminergic and glutamatergic neurotransmission within the brain’s reward circuitry, which includes medium spiny neurons of the striatum. Two classes of dopamine receptors important for reward serve as principle targets of drugs abuse, which interact with glutamate receptor signaling critical for reward learning mechanisms. Complex networks of intracellular signal transduction mechanisms underlying these receptors are strongly stimulated by addictive drugs.
Through these mechanisms, repeated drug exposure alters functional and structural neuroplasticity, resulting in transition to the addicted biological state and behavioral outcomes that typify addiction. Ca2+ and cAMP represent key second messengers that initiate signaling cascades, which regulate synaptic strength and neuronal excitability. Protein phosphorylation and dephosphorylation are fundamental mechanisms underlying synaptic plasticity that are dysregulated by drugs of abuse. By identifying and understanding novel regulatory mechanisms by which protein kinases and phosphatases exert their effects during normal reward learning and the addiction process we hope to reveal novel targets for the development of pharmacotherapeutics with increased efficacy in promoting abstinence and decreased side effects, such as interference with natural reward, for drug addiction.
See the following publication to learn more about our drug addiction research:
Philibin, S.D., Hernandez, A., Self, D.W., and J.A. Bibb (2011) Striatal signal transduction underlying drug addiction: behavior, neuroplasticity, and molecular perspectives, Frontiers in Neuroanatomy 5:60.
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.
Bibb, J.A., Mayford, M.R., Tsien, J.Z., Alberini, C.M. (2010) Cognition Enhancement Strategies, J. Neurosci. 30:14987-92.
Meyer, D.A., Richer, E., Benkovic, S.A. Janice W. Kansy, J.W., Hale, C., Moy, L. Kim, Y., James P. O’Callaghan, J.P. Li-Huei Tsai, L.-H., Paul Greengard, P. Angus C. Nairn, A.C., Cowan, C.W. Diane B. Miller, D.B., Antich, P., Bibb, J.A. (2008) Striatal dysregulation of Cdk5 alters locomotor responses to cocaine, motor learning, and dendritic morphology, PNAS 105:18561–18566.
Benavides, D.R., Quinn, J.J., Zhong, P., Hawasli, A.H., DiLeone, R.J., Kansy, J.W., Olausson, P., Yan, Z., Taylor, J.R., and Bibb, J.A. (2007) Cdk5 controls cocaine reward, motivation, and striatal neuron excitability. J. Neurosci. 27:12967-12976.
Taylor, J.R., Lynch, W.J., Sanchez, H., Oausson, Pl, Nestler, E.J., and Bibb, J.A. (2007) Inhibition of cyclin dependent kinase 5 in the nucleus accumbens enhances the locomotor activating and incentive motivational effects of cocaine. Proc. Natl. Acad. Sci. USA, 104: 4147-4152
Sahin, B., Galdi, S., Hendrick, J. Greene, R.W., Snyder, G.L., and Bibb, J.A. (2007) Evaluation of neuronal phosphoproteins as mediators of striatal adenosine A2A receptor signaling and the actions of caffeine. Brain Research1129:1-14.
Bibb, J.A. (2005) Decoding Dopamine Signaling. Cell 122:153-155.
Kansy, J., Daubner, S.C., Nishi, A., Soogaku, N., Lloyd, M.D., Nguyen, C., Lu, L., Haycock , J., Hope, B.T., Fitzpatrick, P.F., and Bibb, J.A. (2004) Identification of tyrosine hydroxylase as a physiological substrate of Cdk5. J. Neurochem. 91: 374-84.
Norholm, S., Bibb, J.A., Ouimet, C.C., Nestler, E.J., Taylor, J.R., and Greengard, P. (2003) Cocaine-induced proliferation of dendritic spines is dependent on the activity of cyclin-dependent kinase 5. Neuroscience 116: 19-22.
Lindskog, M., Pozzi, L., Svenningsson, P., Fienberg, A., Bibb, J.A., Fredholm, B.B., Greengard, P., Fisone, G. (2002), The stimulant action of caffeine is mediated by an increase in the state of phosphorylation at the Cdk5 site of DARPP-32. Nature 428:7 74-748.
Bibb, J.A., Chen, J., Taylor, J.R., Svenningsson, P., Nishi, A., Snyder, G.L., Yan, Z., Sagawa, Z.K., Nairn, A.C., Nestler, E.J., and Greengard, P. (2001) Regulation of the effects of cocaine by Cdk5 in dopaminoceptive neurons in the brain. Nature 410: 376-380.