Description of Research Expertise

KEY WORDS:
gene targeting, mouse models, behavioral genetics, CRE-transcription factors (CREB, CREM, ICER), substance abuse, depression

RESEARCH INTERESTS
Molecular Basis of Addiction and Depression

RESEARCH TECHNIQUES
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

RESEARCH SUMMARY
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.