[log in to unmask]" type="cite"> 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
           Prince William Campus
 
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 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:

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.

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