Evaluation of GABA in impulsivity and nicotine dependence
Initial Award Abstract
Tobacco smoking, attributed primarily to the addictive properties of nicotine contained in tobacco smoke, continues to be a worldwide problem of drug abuse with serious effects in health leading to several hundred thousand deaths per year in the USA alone. The cost to society is uncountable, considering the health problems that lead to human suffering, medical costs and death. A recent study sponsored by the World Health Organization and the World Bank estimates that in high income countries smoking-related healthcare expenses account for 6-15% of all annual healthcare costs. In addition, it has been projected that by the year 2020 tobacco smoking will become the largest single health problem worldwide, leading to approximately 8.4 million deaths annually. Taking into consideration the fact that the risk for developing diseases associated with tobacco smoking is reduced when smoking is stopped, there is a strong need and incentive to conduct high quality biomedical research aiming at discovering more effective prevention and cessation treatment strategies than the ones currently available.
The present fellowship application addresses the tobacco smoking problem by proposing the conduct of biomedical research that will help us improve our understanding of the potential contribution of the impulsivity personality traits to different aspects of nicotine dependence. Impulsivity, which is defined as a tendency to pursue rewarding stimuli without consideration for potential harmful effects or negative consequences, has been shown to be strongly associated with habitual tobacco smoking. Recent findings indicate that high levels of impulsivity may be a risk factor and one of the mechanisms that leads to the initiation and maintenance of tobacco smoking, as well as craving and relapse after nicotine abstinence. Little is known, however, about the role of the brain endogenous substances γ-aminobutyric acid (GABA) and glutamate on impulsivity and, more importantly, on the effects of drugs that mimic or block the action of this endogenous brain substances on the rewarding effects of nicotine in high and low impulsive individuals.
The first set of the proposed studies focuses on determining GABA and glutamate levels in two specific brain sites, the medial prefrontal cortex and the nucleus accumbens core, that are highly implicated in impulsivity. The studies will be conducted in high and low impulsive subjects with or without acute exposure to nicotine. Nicotine is the main psychoactive ingredient in tobacco smoke responsible for the habitual tobacco smoking habit. The second set of studies will explore the potential differential effects of a drug that mimics the endogenous actions of GABA or one that inhibits the endogenous action of glutamate on different behaviors that are relevant to nicotine dependence. The results from the proposed studies could potentially influence our approach to drug discovery by suggesting that different types of therapeutic compounds are prescribed to smokers with different personality traits, such as high and low impulsive smokers. Taken together, these studies will provide us with valuable information that will promote our understanding of the brain mechanisms that mediate nicotine dependence and help us design effective treatments for smokers with different personality traits. |