Brain adaptations to chronic nicotine expsoure
Abstracts
Initial Award Abstract |
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The majority of adult smokers start smoking as children. Although it has been believed that adolescents smoke for social reasons and do not inhale, recent studies suggest that as many teenagers are addicted to cigarettes as are adults. In order to develop effective therapies for treatment of nicotine addiction in adults and children, it is necessary to first understand the brain mechanisms underlying the compulsion to smoke. This is the subject of the present proposal.
Studies in animals have shown that nicotine is like many other drugs of abuse in that it stimulates the activity of nerve pathways to the striatal region of the brain which contain the neurotransmitter, dopamine. Activation of these dopamine pathways underlies the rewarding effect of the drug. As with other addictive drugs, repeated exposure to nicotine causes increased sensitivity to the behavioral effects of the drug. This "sensitization", which stimulates increased drug-seeking behavior, is believed to result from adaptive changes in brain function. We propose to examine this issue by measuring the effects of single and repeated nicotine injections in rats. We will test the hypothesis that nicotine induces similar changes in gene expression as those induced by other abused drugs, such as morphine, amphetamine and cocaine. We will also examine the status of brain nicotinic receptors and dopamine pathways following repeated nicotine treatments.
mechanisms underlying the compulsion to smoke. This is the subject of the present proposal.
The neurochemical changes within the brain will be compared with behavioral changes in the same animals. In addition to studying adult rats, we will also examine the effects of nicotine on the brains of male and female rats at different times after birth. We will test the hypothesis that nicotine activates dopamine systems in immature brain and produces long-term changes in brain function. Since clinical data suggest that girls are at somewhat higher risk for smoking than boys, we will also determine whether there are sex differences in nicotine's effects on immature brain function. Taken together the data generated from this study should provide critical insight into the mechanisms underlying nicotine addiction, both in children and adults. |
Final Report |
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There is now much evidence that smoking is addictive, with a large majority of smokers failing to quit after repeated attempts. Many adult smokers initiate smoking behavior as adolescents. Although it has previously been believed that smoking in children is a social activity, and that the majority of young smokers do not inhale, recent studies have provided evidence to the contrary. In light of finding that similar proportion of teenagers are addicted to cigarettes as are adults, a critical analysis of underlying mechanisms is essential. Both human and animal studies have shown that nicotine is the active component which mediates tobacco dependence. Nicotine acts as a positive reinforcer, at least partially through stimulation of mesolimbic dopamine systems. As with other drugs of abuse, chronic, intermittent nicotine exposure results in sensitization to the behavioral effects of the drug. This sensitization, which is believed to underlie caving and increased drug-seeking behavior, results from adaptive changes in the brain. Current theories of nicotine addiction are largely focused on plasticity at the level of the nicotinic receptor. In contrast, theories for other drugs of abuse focus on adaptive changes in target neurons. The aim of the present proposal is to use quantitative in situ hybridization to determine whether acute and chronic nicotine treatments induce similar changes in striatal gene expression as have been shown for other abused drugs. The particular targets for analysis will include the immediate early gene, cfos, and the opioid peptides, dynorphin and enkephalin. Using in vitro neurotransmitter release and [3H]epibatidine binding assays, we will also determine the status of mesolimbic dopaminergic transmission and nicotinic receptor function in chronically treated animals. In order to correlate neurochemical changes with behavior, drug-induced locomotor activity will be examined in parallel. In addition to studying adult rats, we will also examine the effects of acute and chronic nicotine treatments on the brains of male and female rat pups at different times after birth. We will test the hypothesis that nicotine activates dopamine systems in immature brain and produces longterm changes in brain function. Since clinical data suggests that girls are at somewhat higher risk for smoking than boys, we will also determine whether there are sex differences in nicotine's effects on immature brain function. Taken together the data generated from this study should provide critical insight into the mechanisms underlying nicotine addiction, both in children and adults. |
