*Dissertation Defense Announcement
To: The George Mason University Community*
*Candidate: Laura L. Locklear
Program: PhD Biosciences
*
*Date: Monday April 25, 2011
Time: 1:00 p.m.
Place: George Mason University
** David King Hall, Room 3006
Fairfax campus <http://www.gmu.edu/resources/visitors/findex.html>
Dissertation Chair: Dr. Karl J. Fryxell
Committee members: Dr. Daniel N. Cox, Dr. Alan Christensen, Dr. Robert F. Smith*
*Title: **"Nicotine Preference and Gene Expression: the Role of /Cd81"/**
*
The dissertation is on reserve in the Johnson Center Library, Fairfax campus.
The doctoral project will not be read at the meeting, but should be read in advance.
/**/All members of the George Mason University community are invited to attend.
*ABSTRACT:
*
Smoking is a leading preventable cause of death worldwide. Variation in
smoking behavior arises in large part from individual perception of
nicotine's rewarding effects, and the propensity for nicotine
dependence. Attempts to elucidate molecular mechanisms underlying these
factors have so far been insufficient for developing effective
treatments for, or reliable predictors of dependence. Thus, identifying
genetic determinants of nicotine addiction is of vital importance. This
can most readily be accomplished using laboratory mice.
We used two-bottle choice nicotine self-selection to assess differences
in nicotine consumption between the C57BL/6J and A/J inbred strains, and
in a separate experiment, C57BL/6J /Cd81/ knockout mouse strains. We
quantified the relative motivation to seek nicotine. Our unique set of
experimental design parameters allowed unprecedented success in
distinguishing between the strains and sexes through voluntary nicotine
consumption. The cohorts exhibited distinct nicotine consumption
levels. Most showed increasing consumption with time, indicating
tolerance effects. We measured signs of nicotine withdrawal in the
C57BL/6J mice, and found without exception, each cohort became nicotine
dependent. Our nicotine self-selection paradigm satisfies all accepted
criteria for animal models of alcoholism. On this basis, we regard our
design as being a valid model for nicotine dependence.
During self-selection, we determined that /Cd81/ loss-of-function
significantly increased nicotine preference. However, previous studies
had indicated /Cd81/ loss-of-function produced a reduction in cocaine
preference. Thus, we investigated further by comparing gene expression
in wild-type and /Cd81/ knockout mice at baseline and after nicotine
treatments. We measured the expression of genes for dopamine receptors
(/Drd1, Drd2_S , Drd2_L , Drd3/), the dopamine transporter (DAT),
phosphodiesterases (/Pde4b, Pde4d/), and the tetraspanin /Cd81/, in the
mesocorticolimbic pathway. Our results indicated the following: (i)
CD81 function was essential for normal transcriptional response to
nicotine, (ii) baseline expression of /Pde4b/ and DAT were each
influenced by /Cd81/ genotype in key brain areas and (iii) the baseline
expression of /Pde4b/ and DAT correlated with nicotine consumption
behaviors. Finally, we speculate that /Cd81/, /Pde4b/ and DAT work in
concert to modulate nicotine preference and that this /Cd81/-associated
pathway may function in a drug-specific manner.
In conclusion, our results support the use of laboratory mice in
nicotine self-selection for assessing nicotine preference. We found
that CD81 influences nicotine consumption and transcriptional activity
of dopamine signaling-associated components. Our hypothesis that CD81,
PDE4B and DAT participate in a single pathway, working in concert to
modulate drug consumption will be tested in future experiments.
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