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The burden of disease and negative economic impact of tobacco addiction on society is considerable. It has been projected that by the Year 2020, tobacco smoking will become the largest single health problem worldwide, causing approximately 8.4 million deaths annually (Murrey & Lopez 1997). Although the harmful health effects from smoking are widely known, only an estimated 3% of smokers quit each year, less than 10% of those who attempt smoking abstinence (Shiffman et al. 1998). Therefore, there is much incentive to develop interventions designed to reduce and prevent tobacco use. To achieve this goal, it is necessary to understand the mechanisms by which tobacco addiction occurs. Determination of the neurochemical substrates mediating nicotine dependence and the genetic factors contributing to nicotine dependence will lead to the development of novel therapeutic agents for the treatment of nicotine addiction. These are critical goals for TRDRP and for international public health in general. Basic science research offers the possibility to examine the mechanisms of nicotine dependence in depth, and to investigate the genetic risk factors for addiction. Such investigations may lead to the development of treatments to eliminate or diminish the tobacco smoking habit in populations around the world. Cessation of tobacco smoking in people dependent on nicotine leads to a withdrawal syndrome characterized by affective or emotional signs, cognitive deficits and somatic signs of withdrawal. The assessment of the emotional and cognitive aspects of withdrawal is important because it is hypothesized that these withdrawal symptoms contribute significantly more to craving, relapse and the maintenance of dependence than the somatic aspects of withdrawal (Kenny & Markou 2001; Markou et al. 1998). The purpose of this grant application is to characterize affective/emotional, cognitive and somatic symptoms of nicotine withdrawal. One of the depression-like emotional symptoms of nicotine withdrawal is a reward deficit expressed as anhedonia (i.e., “inability to experience pleasure” in rewarding stimuli; American Psychiatric Association 1994). A model of “reward deficits” will be used in the proposed studies. This model utilizes the intracranial self-stimulation procedure which provides a valid, reliable and quantitative measure of the emotional aspects of nicotine withdrawal (that is, reward thresholds). Other emotional symptoms of nicotine withdrawal in humans include increased anxiety (American Psychiatric Association 1994; Hughes et al. 1994). The acoustic startle response reflects reactivity to environmental stimuli and startle reactivity is increased when the subject is in an anxious state (Grillon 2002; Bast & Feldon 2003). Proposed studies will characterize anxiety-like behavior and startle response using the light-dark box and the startle tests, respectively. Further, cognitive and attentional deficits are reported by people during nicotine withdrawal (Pomerleau 1997; Hatsukami et al. 1989; Jacobsen et al. 2005). Presentation of a weak pre-stimulus prior to the startle-eliciting stimulus, reliably and robustly decreases the magnitude of the subsequent startle response, a phenomenon called prepulse inhibition (PPI). PPI of the acoustic startle response is a measure of the loss of sensorimotor gating that may contribute to cognitive deficits (Swerdlow & Geyer 1998). Proposed studies will investigate the effects of nicotine withdrawal on cognitive deficit measured by PPI. Additionally, proposed studies will characterize somatic signs of nicotine withdrawal reflecting the ‘physical’ aspects of nicotine dependence. The investigation of strain differences in the expression of these emotional, cognitive and “physical” signs of nicotine withdrawal will promote our knowledge of genetic influences in the development of nicotine dependence and addiction. In summary, the proposed studies will develop measures of nicotine withdrawal that may allow assessment of potential therapeutic treatments on the emotional, cognitive and “physical” aspects of nicotine withdrawal (a TRDRP research priority), and the potential contribution of genetic factors to the expression of the various aspects of the nicotine withdrawal syndrome. The proposed measures of nicotine withdrawal have translational value because they assess brain reward function, anxiety-like behavior, cognitive deficits and somatic signs that are believed to be dysregulated during nicotine withdrawal in humans. Thus, these studies will develop and validate experimental measures that can be used to promote our understanding of the mechanisms mediating the nicotine withdrawal syndrome, which is another TRDRP research priority. |
