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Dissertation Defense Announcement
To: The George Mason University Community
Candidate: Nachiket Dharker
Program: PhD Biosciences
Date: Wednesday August 8, 2012
Time: 2:00 p.m.
Place: George Mason University
Occoquan Bldg., #203
Dissertation Director/Committee Chair: Dr. Karl J. Fryxell
Committee members: Dr. Ancha Baranova, Dr.
Daniel N. Cox, Dr. Timothy Born
Title: "Gene Expression Responses to Single and Repeated Nicotine
Injections in Adolescent and Adult Mice"
The dissertation is on reserve in the Johnson Center Library, Fairfax
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
The majority of smokers begin tobacco use during adolescence.
Relatively little is understood about the molecular effects of nicotine
on adolescents and its role in establishing future nicotine dependence.
Here we studied the mRNA expression of dopamine receptors (Drd1, Drd2S,
Drd2L, Drd3), cyclic nucleotide phosphodiesterases [Pde4b (long
isoforms), Pde4b1, Pde4d ], a tetraspanin (Cd81), opioid peptides (Pdyn
and Penk), and the anaplastic lymphoma kinase receptor (Alk) after
single or repeated nicotine injections in brain areas of mice by
quantitative reverse transcriptase PCR. We found that a single nicotine
injection caused dramatic gene expression responses in the adolescent
medial prefrontal cortex, where all inhibitory dopamine receptor mRNAs
(Drd2L, Drd2S, and Drd3) decreased by an average of 3.5-fold after 24
hr in adolescents but not in adults. The downregulation of Drd2 in
adolescent males and females of the A/J and C57BL/6J strains was
strongly correlated (r = 0.99) with the nicotine preference of those
sexes and strains (measured as adults). More generally, we found
adolescent-specific gene expression responses to nicotine in Drd2,
Drd3, Pde4b (long isoforms), Alk, and Penk in medial prefrontal cortex,
and in Pde4b1 and Pde4d in ventral striatum. We also found
adolescent-specific sexually divergent gene expression responses of
Cd81. Another interesting finding was the significant correlation
between Drd2 and Penk expression in medial prefrontal cortex (but not
Drd1 and/or Pdyn). In contrast to the responses to a single nicotine
injection, repeated nicotine injections produced significant gene
expression responses for many of these genes in ventral striatum that
differed significantly between adolescents and adults. In fact, the
expression of Drd2S, and Drd2L decreased after repeated nicotine
injections in all adolescent sexes and strains, but increased in most
sexes and strains of adult ventral striatum. Moreover, nicotine-induced
changes in gene expression of all other genes in ventral striatum were
specific to adults. In medial prefrontal cortex, fewer genes (Drd1 and
Drd3) showed differential gene expression responses between adolescents
and adults, and none of these gene expression responses were
adolescent-specific. Our results suggest that the initial
adolescent-specific component of the gene expression responses to
nicotine occurs primarily in medial prefrontal cortex, but the
responses to repeated nicotine injections occur primarily in ventral
striatum. Results from other brain areas are also reported. Our results
help to elucidate several steps of adolescent-specific gene expression
response to nicotine by genes that are implicated in drug abuse.