The goal of this project is to elucidate the molecular mediators that lead to the association of contextual cues with the nicotine experience, a critical step in the process toward understanding and curing nicotine addiction.  Nicotine addiction is accompanied by striking associations between tobacco use and the context in which it is being experienced making it particularly difficult to maintain abstinence.  This problem is a significant health and social issue because tobacco use is the leading cause of preventable death in the United States.

Manipulation of the key mediators of these nicotine – context associations will facilitate their dissociation.  Since ERK MAPK plays a pivotal role in hippocampus-dependent contextual associative learning, and since nicotine both activates ERK MAPK in hippocampus and enhances hippocampus-dependent associative learning, we hypothesize that manipulations of ERK MAPK during different phases of nicotine – context associative learning will alter expression of those associations and hence enhance the extinction process.  Compulsion to take drugs of abuse and risk of relapse is, in part, an associative learning issue.   Pavlovian conditioning, one form of associative learning, describes the process by which a neutral stimulus becomes associated with a rewarding stimulus following repeated pairing of the two. For example the addictive drug nicotine serves as an unconditioned stimulus (US) that provides an unconditioned reward (UCR). After repeated pairings of nicotine with neutral environmental stimuli, these neutral stimuli gain significance (conditioned stimuli, CS).  As such, the context in which nicotine is repeatedly experienced becomes a CS associated with nicotine delivery and thus an important part of the stimulus complex that sustains nicotine use.

Nicotine-conditioned locomotor stimulation is a straightforward behavioral paradigm based on Pavlovian conditioning principles and serves as a model for nicotine – context associative learning.  We have utilized this paradigm to study the nicotine – context associative learning processes involved in the development, expression, and extinction of nicotine-conditioned cues.  We tested the hypothesis  that ERK MAPK inhibition immediately following retrieval (expression) of nicotine - context associative learning and found that this manipulation  enhances the extinction process. Future work will focus on the specific brain regions and the upstream/downstream mediators of this phenomenon.