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.
Hussmann G Patrick, Dedominicis Kristen E, Turner Jill R, Yasuda Robert P, Klehm Jacquelyn, Forcelli Patrick A, Xiao Yingxian, Richardson Janell R, Sahibzada Niaz, Wolfe Barry B, Lindstrom Jon, Blendy Julie A, Kellar Kenneth J: Chronic Sazetidine-A Maintains Anxiolytic Effects and Slower Weight Gain Following Chronic Nicotine Without Maintaining Increased Density of Nicotinic Receptors in Rodent Brain. Journal of Neurochemistry Page: Epub ahead of print, Jan 2014.
Jochems Jeanine, Boulden Janette, Lee Bridgin G, Blendy Julie A, Jarpe Matthew, Mazitschek Ralph, Van Duzer John H, Jones Simon, Berton Olivier: Antidepressant-Like Properties of Novel HDAC6-Selective Inhibitors with Improved Brain Bioavailability. Neuropsychopharmacology 39(2): 389-400, Jan 2014.
Turner J R, Ray R, Lee B, Everett L, Xiang J, Jepson C, Kaestner K H, Lerman C, Blendy J A: Evidence from mouse and man for a role of neuregulin 3 in nicotine dependence. Molecular psychiatry Page: Epub ahead of print, Sep 2013.
Turner Jill R, Wilkinson Derek S, Poole Rachel Lf, Gould Thomas J, Carlson Gregory C, Blendy Julie A: Divergent functional effects of sazetidine-a and varenicline during nicotine withdrawal. Neuropsychopharmacology 38(10): 2035-47, Sep 2013.
Gundersen Brigitta B, Briand Lisa A, Onksen Jennifer L, Lelay John, Kaestner Klaus H, Blendy Julie A: Increased hippocampal neurogenesis and accelerated response to antidepressants in mice with specific deletion of CREB in the hippocampus: role of cAMP response-element modulator τ. The Journal of Neuroscience 33(34): 13673-85, Aug 2013.
Briand Lisa A, Blendy Julie A: Not all stress is equal: CREB is not necessary for restraint stress reinstatement of cocaine-conditioned reward. Behavioural brain research 246: 63-8, Jun 2013.
Balu Darrick T, Turner Jill R, Brookshire Bethany R, Hill-Smith Tiffany E, Blendy Julie A, Lucki Irwin: Brain monoamines and antidepressant-like responses in MRL/MpJ versus C57BL/6J mice. Neuropharmacology 67: 503-10, Apr 2013.
Turner Jill R, Gold Allison, Schnoll Robert, Blendy Julie A: Translational research in nicotine dependence. Cold Spring Harbor perspectives in medicine 3(3): a012153, Mar 2013.
Turner Jill R, Ecke Laurel E, Briand Lisa A, Haydon Philip G, Blendy Julie A: Cocaine-related behaviors in mice with deficient gliotransmission. Psychopharmacology 226(1): 167-76, Mar 2013.
Wilkinson Derek S, Turner Jill R, Blendy Julie A, Gould Thomas J: Genetic background influences the effects of withdrawal from chronic nicotine on learning and high-affinity nicotinic acetylcholine receptor binding in the dorsal and ventral hippocampus. Psychopharmacology 225(1): 201-8, Jan 2013.
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Last updated: 01/21/2014
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