gene targeting, mouse models, behavioral genetics, CRE-transcription factors (CREB, CREM, ICER), substance abuse, depression
Molecular Basis of Addiction and Depression
Generation of mouse models using the approaches of gene targeting in embryonic stem cells. Characterization of these mouse models by1) behavioral analysis: locomotor activity, morphine withdrawal response, Conditioned Place Preference, forced swim test, tail suspension test. 2) pharmacological analysis 3) molecular analysis: RNAse protection assays, real time PCR, EMSA, Western blots and immunohistochemistry
My research is aimed at understanding the molecular basis for the biochemical and behavioral changes associated with chronic drug use. How drugs exert effects that lead to long-term adaptations within the central nervous system is not well understood. However, alterations in gene expression are a likely mechanism. A group of transcription factors, CREB (cAMP response element binding protein) and CREM (cAMP response element modulatory protein), have been identified as key proteins mediating a transcriptional response to elevated levels of cAMP and/or Ca++. We have shown that mice deficient in CREB show paradoxical responses in behavioral conditioning paradigms to morphine and cocaine. Current projects are aimed at investigating the molecular basis for this differential response with techniques ranging from EMSA's (electromobility shift assays), Western analyses, real time PCR, RNAse protection assays and immunohistochemistry. In addition, recent studies in our lab have identified alterations in depression-like phenotypes in CREB deficient mice, The clinical co-morbidity between addiction and depression is striking. While little is known regarding the cause-effect relationship between these disease states, there are striking similarities at a molecular level, and, as in the case of drugs of abuse, cAMP mediated gene transcription has been implicated in the mechanism(s) of action of antidepressant drugs. Future studies involve the development and use of tissue specific gene-targeting (Cre/loxP system) to inactivate known and/or novel CREB targets to further characterize the molecules and neural circuitry involved in the mechanism of action of drugs of abuse as well as antidepressant drugs. The combined use of pharmacological, behavioral and molecular studies should lead to a better understanding of the biological basis of addiction and depression.
Forcelli Patrick A, Turner Jill R, Lee Bridgin G, Olson Thao T, Xie Teresa, Xiao Yingxian, Blendy Julie A, Kellar Kenneth J: Anxiolytic- and antidepressant-like effects of the methadone metabolite 2-ethyl-5-methyl-3,3-diphenyl-1-pyrroline (EMDP). Neuropharmacology 101: 46-56, Feb 2016.
Falcone Mary, Lee Bridgin, Lerman Caryn, Blendy Julie A: Translational Research on Nicotine Dependence. Current topics in behavioral neurosciences Feb 2016.
Lee Bridgin G, Anastasia Agustin, Hempstead Barbara L, Lee Francis S, Blendy Julie A: Effects of the BDNF Val66Met Polymorphism on Anxiety-Like Behavior Following Nicotine Withdrawal in Mice. Nicotine & tobacco research : official journal of the Society for Research on Nicotine and Tobacco 17(12): 1428-35, Dec 2015.
Yohn Nicole L, Bartolomei Marisa S, Blendy Julie A: Multigenerational and transgenerational inheritance of drug exposure: The effects of alcohol, opiates, cocaine, marijuana, and nicotine. Progress in biophysics and molecular biology 118(1-2): 21-33, Jul 2015.
Zhang Yong, Picetti Roberto, Butelman Eduardo R, Ho Ann, Blendy Julie A, Kreek Mary Jeanne: Mouse model of the OPRM1 (A118G) polymorphism: differential heroin self-administration behavior compared with wild-type mice. Neuropsychopharmacology : official publication of the American College of Neuropsychopharmacology 40(5): 1091-100, Apr 2015.
Briand Lisa A, Lee Bridgin G, Lelay John, Kaestner Klaus H, Blendy Julie A: Serine 133 phosphorylation is not required for hippocampal CREB-mediated transcription and behavior. Learning & memory (Cold Spring Harbor, N.Y.) 22(2): 109-15, Feb 2015.
Briand Lisa A, Hilario Monica, Dow Holly C, Brodkin Edward S, Blendy Julie A, Berton Olivier: Mouse model of OPRM1 (A118G) polymorphism increases sociability and dominance and confers resilience to social defeat. The Journal of neuroscience : the official journal of the Society for Neuroscience 35(8): 3582-90, Feb 2015.
Goffin Darren, Brodkin Edward S, Blendy Julie A, Siegel Steve J, Zhou Zhaolan: Cellular origins of auditory event-related potential deficits in Rett syndrome. Nature neuroscience 17(6): 804-6, Jun 2014.
Ting Jenhao H, Marks David R, Schleidt Stephanie S, Wu Joanna N, Zyskind Jacob W, Lindl Kathryn A, Blendy Julie A, Pierce R Christopher, Jordan-Sciutto Kelly L: Targeted gene mutation of E2F1 evokes age-dependent synaptic disruption and behavioral deficits. Journal of neurochemistry 129(5): 850-63, Jun 2014.
Yohn Nicole L, Turner Jill R, Blendy Julie A: Activation of α4β2*/α6β2* nicotinic receptors alleviates anxiety during nicotine withdrawal without upregulating nicotinic receptors. The Journal of pharmacology and experimental therapeutics 349(2): 348-54, May 2014.
back to top
Last updated: 02/29/2016
The Trustees of the University of Pennsylvania