My research is focused on the neurobiology of motivational systems, and how these systems adapt during the addiction process to regulate addictive behavior. Studies utilize a highly integrative molecular/systems/behavioral approach to investigate the neural substrates of motivation and addiction. Our experiments are aimed at 1) understanding the neural systems that mediate reward and craving, 2) identifying neuroadaptations in these systems that result from the drug addiction process, and, 3) functional studies that determine whether these neuroadaptations actually contribute to addictive behavior itself.
Current projects are investigating the role of dopamine receptor-regulated cAMP-dependent protein phosphorylation in drug self-administration, craving and relapse. These projects study in vivo protein phosphorylation states that coincide with the transition from initial drug use to addiction, and are associated with states of craving. Complementary studies utilize inducible transgenic mice and viral-mediated gene transfer to study the functional role of cAMP-dependent phosphorylation, and transcription factors such as CREB and deltaFosB, in specific neuronal cell types and brain pathways in addiction-related changes in drug self-administration craving and relapse, since these molecular systems are regulated by chronic drug exposure. Other studies investigate the role of drug-induced neuroplasticity in excitatory (glutamatergic) synapses in limbic brain nuclei in the regulation of addictive behavior using viral-mediated gene transfer to modulate AMPA receptor function similar to LTP and LTD.
A final major project has utilized microarrays to identify very long-term changes in gene expression in limbic brain regions following addiction to cocaine, and how extinction learning procedures can modify these changes. In some cases, these basic findings are used to investigate novel behavioral and pharmacological treatments for drug addiction.
RESEARCH INTERESTS
Behavioral Neuroscience
Neuropharmacology
Systems Neuroscience
Neurobiology of Addiction
RECENT PUBLICATIONS
Graham, D.L., Edwards, S., Bachtell, R.K., DiLeone, R.J, Rios, M. and Self, D.W., "Dynamic BDNF activity in nucleus accumbens with cocaine use increases self-administration and relapse." Nature Neurosci., on line 2007
Edwards, S., Graham, D.L., Bachtell, R.K. and Self, D.W., "Region-specific tolerance to cocaine-regulated cAMP-dependent protein phosphorylation following chronic self-administration." Eur. J. Neurosci, 25:2201-2213, 2007
Edwards, S., Whisler, K.N., Fuller. D.C., Orsulak, P.J. and Self, D.W., "Addiction-related alterations in D1 and D2 dopamine receptor behavioral responses following chronic cocaine self-administration." Neuropsychopharmacology, 32:354-366, 2007
Choi, K-H., Whisler, K., Graham, D. and Self, D.W., "Antisense-induced reduction in nucleus accumbens cyclic AMP response element binding protein attenuates cocaine reinforcement." Neuroscience, 137:373-383, 2006
Sutton, M.A., Schmidt, E.F., Choi, K-H., Schad, C.A., Whisler, K., Simmons, D., Karanian, D.A., Monteggia, L.M., Neve, R.L. and Self, D.W., "Extinction-induced up-regulation in AMPA receptors reduces cocaine-seeking behavior." Nature, 421:70-75, 2003
SIGNIFICANT PUBLICATIONS
Self, D.W., "Molecular and genetic approaches for behavioral analysis of protein function" Biological Psychiatry, 57:1479-1484, 2005
Self, D.W., "Regulation of drug-taking and ?seeking behaviors by neuroadaptations in the mesolimbic dopamine system." Neuropharmacology, 47S1:242-255, 2005
Self, D.W. Choi, K-H., Simmons, D., Walker, J.R. and Smagula, C.S., "Extinction training regulates neuroadaptive responses to withdrawal from chronic cocaine self-administration." Learning and Memory, 11:648-657, 2004
Colby, C.R., Whisler, K., Steffen, C., Nestler, E.J., Self, D.W., "Striatal cell type-specific overexpression of ?FosB enhances incentive for cocaine." J. Neurosci., 23:2488-2493, 2003
Self, D.W., Barnhart, W.J., Lehman, D.A. and Nestler, E.J., "Opposite modulation of cocaine-seeking behavior by D1- and D2-like dopamine receptor agonists." Science, 271:1586-1589, 1996
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