• Hiroi, Noboru (PI)

Project: Research project

Project Details


DESCRIPTION(Adapted from applicant's abstract):
The molecular basis of drug addiction has recently been explored using
knock-out mice. These studies have revealed that a number of molecules
contribute to distinct aspects of addiction to stimulants, opiates, and
ethanol. However, the molecular basis of nicotine addiction remains unclear
despite the fact that addiction to nicotine and other drugs shares a common
neuroanatomical basis. The transcription factor FosB and the protein
phosphatase inhibitor DARPP-32 (dopamine- and cAMP-regulated phosphoprotein of
32 kDa) have been shown to be critical determinants for different aspects of
behavioral responsiveness to cocaine in mice. These two intracellular molecules
are unique in that their disruption makes animals more vulnerable to cocaine's
behavioral effects. The present application is designed to test the hypothesis
that these two molecules are also critical for nicotine addiction and that, if
so, they play distinct roles in specific aspects of nicotine dependence.

The experimental design is unique in three aspects. First, a number of
behavioral models will be used to assess different aspects of nicotine
addiction. They include tolerance, sensitization, conditioned place preference,
withdrawal-associated conditioned place aversion, and self-administration.
Second, an attempt will be made to assess the influence of genetic backgrounds
on behavioral phenotypes. The dissimilar genetic backgrounds of knock-out and
wild-type mice littermates have confounded the behavioral phenotypes of
knock-out mice. Heterozygous mice will be repeatedly back-crossed to C57BL/6J
mice to achieve a higher degree of similarity in the genetic backgrounds of
knock-out mice and wild-type littermates (i.e., congenic mice). Third,
anatomical analysis will determine the involvement of neuroanatomical
adaptations in behavioral phenotypes. Based on the outcome of similar
approaches to cocaine addiction, it is expected that these two genes contribute
to specific aspects of nicotine addiction. If these molecules turn out to be
important for vulnerability to nicotine addiction, this mouse study will
provide a solid basis for genetic analysis of human addiction vulnerability.
Effective start/end date8/1/004/30/06


  • National Institute on Drug Abuse: $250,500.00


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