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.
Ray Riju, Ruparel Kosha, Newberg Andrew, Wileyto E Paul, Loughead James W, Divgi Chaitanya, Blendy Julie A, Logan Jean, Zubieta Jon-Kar, Lerman Caryn: Human Mu Opioid Receptor (OPRM1 A118G) polymorphism is associated with brain mu-opioid receptor binding potential in smokers. Proceedings of the National Academy of Sciences of the United States of America 108(22): 9268-73, May 2011.
Onksen Jennifer L, Brown Eric J, Blendy Julie A: Selective deletion of a cell cycle checkpoint kinase (ATR) reduces neurogenesis and alters responses in rodent models of behavioral affect. Neuropsychopharmacology : official publication of the American College of Neuropsychopharmacology 36(5): 960-9, Apr 2011.
Turner Jill R, Castellano Laura M, Blendy Julie A: Parallel anxiolytic-like effects and upregulation of neuronal nicotinic acetylcholine receptors following chronic nicotine and varenicline. Nicotine & tobacco research : official journal of the Society for Research on Nicotine and Tobacco 13(1): 41-6, Jan 2011.
Blendy Julie A: Modeling neuropsychiatric disease-relevant human SNPs in mice. Neuropsychopharmacology : official publication of the American College of Neuropsychopharmacology 36(1): 364-5, Jan 2011.
Ecke Laurel E, Cleck Jessica N, White Peter, Schug Jonathan, Mifflin Lauren, Blendy Julie A: CREB-mediated alterations in the amygdala transcriptome: coordinated regulation of immune response genes following cocaine. The international journal of neuropsychopharmacology / official scientific journal of the Collegium Internationale Neuropsychopharmacologicum (CINP) Page: 1-16, Dec 2010.
Briand Lisa A, Vassoler Fair M, Pierce R Christopher, Valentino Rita J, Blendy Julie A: Ventral tegmental afferents in stress-induced reinstatement: the role of cAMP response element-binding protein. The Journal of neuroscience : the official journal of the Society for Neuroscience 30(48): 16149-59, Dec 2010.
Mombereau Cedric, Kawahara Yukio, Gundersen Brigitta B, Nishikura Kazuko, Blendy Julie A: Functional relevance of serotonin 2C receptor mRNA editing in antidepressant- and anxiety-like behaviors. Neuropharmacology 59(6): 468-73, Nov 2010.
Turner Jill R, Castellano Laura M, Blendy Julie A: Nicotinic partial agonists varenicline and sazetidine-A have differential effects on affective behavior. The Journal of pharmacology and experimental therapeutics 334(2): 665-72, Aug 2010.
Mague Stephen D, Blendy Julie A: OPRM1 SNP (A118G): involvement in disease development, treatment response, and animal models. Drug and alcohol dependence 108(3): 172-82, May 2010.
Mombereau C, Gur TL, Onksen J, Blendy JA: Differential effects of acute and repeated citalopram in mouse models of anxiety and depression. Int J Neuropsychopharmacol 13: 321-334, 2010.
back to top
Last updated: 07/23/2012
The Trustees of the University of Pennsylvania