||5R21CA081649-02 Interpret this number
||University Of Texas Md Anderson Can Ctr
||Genetic Factors in the Modulation of Mood By Nicotine
The specific aims of this project are to determine the effects of
nicotine administration and deprivation on changes in emotional
processing among smokers carrying the DRD2 A1 and A2 alleles.
Data from our laboratory suggest that smokers carrying the A1
allele vs. those with only the A2, are both less likely to quit
smoking and experience less consistent negative affect reduction
when exposed to a treatment involving antidepressant
(venlafaxine) therapy. This suggests that the A1 allele may
modulate the effects of a psychotropic agent on mood while
quitting, and by implication may influence the direction and
magnitude of affective changes associated with nicotine exposure.
Understanding the relationship between genetic factors, nicotine
and mood, may help us identify the most salient properties of
smoking for particular groups of individuals (e.g., positive mood
enhancement, negative affect reduction), and select treatments
which seek to alter this relationship in a beneficial way (e.g.,
reinforcement blockade and mood modulating drugs). However,
procedures for studying the effects of nicotine on mood have
largely been limited to self-report. While important, these
methods rely heavily on cognitive appraisal and cannot assess the
near instantaneous neurophysiological activity thought to precede
a change in affect. In this study, we will use the startle
response as an index of reactivity to affective stimuli. The
startle reflex (eye blink) is an orienting response that follows
an unexpected auditory stimulus (startle probe), and may reflect
immediate changes in underlying cortical and subcortical
processes associated with drive or motivational states (e.g.,
appetitive/defensive; approach/avoidance). Negative emotional
cues delivered prior to the probe increase the blink response
magnitude (eye muscle EMG), while positive cues reduce or inhibit
the response. This startle-affect relationship provides an ideal
paradigm for studying the effects of acute nicotine
administration and withdrawal on mood and allows comparisons
between smokers with more or less vulnerability to become
nicotine dependent (e.g. A1 allele types) and/or those who may
have more difficulty quitting. Using a 2x2x2x3 factorial design,
we will determine if the magnitude and latency of the startle
response is influenced by genotype (A1/A1 and A1/A2 or A2/A2),
level of nicotine withdrawal (overnight deprived or non-
deprived), acute administration of nicotine (nicotine or
placebo), and the affective valance (positive, negative, neutral)
of emotional stimuli. Two groups of smokers (60 with and without
the A1 allele), stratified by race, gender and depression
history, will be exposed to four counterbalanced laboratory
assessments, completely crossing the 2 levels of pre-session
nicotine withdrawal (deprivation/non-deprived) with 2 levels of
within session drug administration (nasal nicotine administration
or placebo). Within each session, participants will receive 2
blocks of startle probe trials, associated with exposure to
emotional cues (standardized slides) selected for 3 levels of
affective valence (positive, negative or neutral). The first
will be preceded by placebo and the second by either nicotine
nasal spray or placebo, depending on the session. Differences in
startle intensity and latency between the first trial block
(placebo) and the second (placebo or nicotine) will be compared
across the four sessions. We hypothesize an enhanced startle
response (increased magnitude/decreased latency) for negative vs
positive cues, presence of the A1 allele (A1/A1 +A2/A1 greater
than A2/A2); deprived vs. nondeprived; and nicotine vs. placebo
conditions. A1 smokers are also expected to show significantly
enhanced responding to negative stimuli and greater attenuation
of responding by nicotine. In exploratory analyses, we will also
assess the modulating effects of other candidate genes (DRD4 and
SLC6A3) on these relationships. Confirmation of these hypotheses
will provide evidence for nicotine's action as a mood modulator
and the importance of genetic factors related to dopamine
neurotransmission in determining the direction and magnitude of
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