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The specific aims of this project are to determine the influence of genetic factors on changes in emotional processing, during the first two weeks of nicotine withdrawal. Treatment studies suggest that difficulty maintaining abstinence during this time frequently leads to relapse. Moreover, the experience of negative affect is a significant contributor to the risk of relapse and comprises a major factor of the nicotine withdrawal syndrome. We will use a standardized laboratory assessment procedure, known as the startle probe, to evaluate the differences in emotional reactivity of smokers carrying the DRD2 A1 or A2 allele. The startle reflex (eye blink) is an orienting response that follows an unexpected auditory stimulus (startle probe). It is thought to reflect immediate changes in cortical and subcortical activity related to drive and motivation, such as approach or defensive behavior. Negative emotional cues, such as slides of upsetting events, delivered prior to the probe, increase blink response magnitude (eye muscle EMG), while positive cues reduce or inhibit the response. This startle-affect relationship provides an ideal paradigm for studying genetic differences between smokers in the disruptive effects of nicotine withdrawal on mood. We choose the DRD2 gene for analysis, since studies suggest it may be related to dopamine responsivity and vulnerability to nicotine dependence and other substance abuse. Data obtained within our earlier SPORE project also shows that smokers with the A1 allele have more difficulty quitting than those with the A2 and that they experience significantly less negative affect reduction with antidepressant therapy, during cessation treatment. However, little is known about the mechanisms through which these genetic differences could contribute to dependence and relapse. A heightened response to negative emotional stimuli during nicotine withdrawal could enhance the risk of relapse and genetic differences among smokers could account variations in this effect. In this study, 120 smokers will be genotyped (60 with the A1 and 60 with only the A2 allele) and randomly assigned to either a Quitter or Control group. After a baseline startle assessment, Quitters will receive behavioral treatment for cessation and will be expected to abstain from smoking for two weeks. Controls receive no treatment and are expected to smoke normally during this time. To determine the effects of nicotine withdrawal on emotional reactivity, startle responses will be compared at baseline and after 1, 7 and 14 days of abstinence for the Quitters, and comparable points for the Controls. Each assessment will involve a series of startle probe trials consisting of the presentation of an acoustic stimulus (startle probe), immediately preceded by positive, negative or neutral emotional cues. We hypothesize an enhanced startle response (increased magnitude decreased latency) for negative versus positive cues, presence versus absence of the A1 allele (A1/A1 +A2/A1 greater than A2/A2) and quitters versus controls. DRD2 A1 quitters versus controls are also expected to show significantly enhanced responding to negative emotional cues during nicotine withdrawal, than A2 quitters versus controls. Results of this research could be used to improve clinical outcome. For example, the startle methodology could be used to identify treatments (e.g., pharmacological agents) likely to have a significant impact on emotional reactivity during cessation, and to discover which treatments work best for particular groups of smokers.
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