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April 2011

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From:
"Diane St. Germain" <[log in to unmask]>
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Date:
Fri, 15 Apr 2011 16:05:06 -0400
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*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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