Molecular Mechanisms of Nicotine Addiction and Extinction

DESCRIPTION (provided by applicant): The long-term objective of the principal investigator is to ascertain the molecular mechanisms underlying nicotine addiction/dependence. One salient aspect of nicotine addiction is that cues that are usually associated with nicotine exert a powerful control over craving and relapse in smokers. Although some attempts have been made to implement cue extinction to aid smoking cessation, lack of knowledge regarding the mechanisms of cue control of smoking has hampered progress. The proposed studies are designed to elucidate the molecular mechanisms underlying extinction of cue control of nicotine addiction in the place conditioning paradigm in mice. This R01 application tests the overall hypothesis that cGMP-dependent protein kinase subtype II (PKG-II), in regions along the mesocorticolimbic dopamine system, is a determinant of the rate of extinction of nicotine-induced conditioned place preference (CPP) in mice. Our published and preliminary studies show that a) nicotine elevates the concentration of cGMP in the striatum (nucleus accumbens and caudate-putamen), b) nicotine can up-regulate PKG activity in the nucleus accumbens and the VTA, which represent a target and the origin of the mesocorticolimbic dopamine pathway, respectively, c) nicotine causes phosphorylation of a PKG substrate in the striatum (including the nucleus accumbens), d) mice exhibit intensified nicotine CPP on the first few drug-free test days and extinction thereafter, and e) extinction of nicotine CPP is accelerated in PKG-II knockout (KO) mice. The proposed studies rely on genetic manipulation of PKG levels in the mouse brain. Specific Aim 1 will test the hypothesis that the level of PKG-II, but not PKG-I, determines the rate of extinction of nicotine CPP. PKG-I and PKG-II wild-type (WT), heterozygous (HT), and KO mice will be employed. Moreover, we will determine the exact behavioral processes in which PKG subtypes play a role during extinction of nicotine CPP and the general role played by PKG subtypes in extinction of cue control by other addictive substances. Specific Aim 2 will identify the specific brain region(s) in which PKG may act to regulate extinction of nicotine CPP. We will use a lentiviral vector to locally restore PKG-II (or PKG-I) in PKG-II (or PKG-I) KO mice. Moreover, we will correlate maintenance of nicotine CPP during extinction with PKG activities in selected brain regions along the mesocorticolimbic dopamine pathway. The outcome of the proposed studies is significant, as it will provide evidence that can be used to devise therapeutic options for smokers. Identification of a PKG subtype in specific brain loci, in connection with cue control of nicotine addiction, would be an important step toward enhancing our ability to fine-tune molecular targets to prevent cue-triggered smoking relapse and accelerate extinction. If this kinase turns out to be important for cue control of other addictive substances during extinction, the outcome of these studies will have a much broader implication for treatment of cue-triggered relapses in other forms of addiction. Recent estimates indicate that there are approximately 1.3 billion smokers world-wide and 5 million deaths are attributable to tobacco use annually. Currently available therapies are not effective in aiding cessation, partly because the exact neuronal mechanisms underlying extinction of nicotine addiction are still poorly understood. The proposed studies are designed to fill in this knowledge gap.