Primary Projects: CREB
The Role of CREB and Opioid System in Nicotine Reward
Project Leader: Julie Blendy, Ph.D.
PROJECT DESCRIPTION: In order to investigate the molecular mechanisms of nicotine dependence and to screen potential intervention therapies, animal models of nicotine addiction are critical. This project uses behavioral, genetic and pharmacological approaches to investigate intracellular signaling events underlying nicotine addiction in mice. Specifically, it will characterize the role of the nuclear transcription factor CREB and the endogenous opioid system in nicotine reward, with particular emphasis on the potential these molecules have to serve as therapeutic targets. It will also investigate the role of CREB in genetic mechanisms underlying nicotine withdrawal. This information, in conjunction with the results of the Extended Patch Trial (detailed below), will increase our understanding of the role of the endogenous opioid system in nicotine dependence and may lead to the development of new therapeutic approaches.
LATEST FINDINGS:
Environmental cues associated with nicotine delivery are an important part of the stimulus that sustain smoking behavior and are often coupled with craving and relapse; however, the neuronal circuitry and molecular substrates underlying this process are still poorly understood. Exposure to an environment previously associated with rewarding properties of nicotine results in an increase of CREB phosphorylation similar to that seen following nicotine administration, and this response is absent in mu-opioid receptor (-/-) mice. Moreover, a single administration of an opioid receptor antagonist, naloxone, blocks both the conditioned molecular response (CREB phosphorylation) and the conditioned behavioral response (nicotine reward) in a place preference paradigm. Lastly, repeated nicotine administration results in increased expression of MORs. However, this effect, along with rewarding properties of nicotine, is blocked in mice with a targeted disruption in the CREB gene. Together, pharmacologic and genetic manipulations indicate that phosphorylation of CREB and upregulation of functional MORs are required for nicotine-conditioned reward.
RELATED PUBLICATIONS:
Walters, C. L., Cleck, J. N., Kuo, Y. C., & Blendy, J. A. (2005). Mu-opioid receptor and CREB activation are required for nicotine reward. Neuron, 46(6), 933-943.
ADDITIONAL CITATIONS:
Blendy JA, Strasser A, Walters CL, Perkins KA, Patterson F, Berkowitz R, Lerman C. Reduced nicotine reward in obesity: cross-comparison in human and mouse. Psychopharmacology. 2005 Jul; 180(2): 306-15.