Recent advances in gene transfer technology have resulted in the ability to either over express or knock out the expression of genes of interest in behaving animals. These powerful techniques make it possible to combine a large body of work on the behavioral pharmacology of drugs of abuse with out evolving knowledge of the molecular biological changes that may underlie these behaviors. We are now able to manipulate the expression of specific gene products, both temporally and spatially in the absence of treatment with drugs of abuse, and observe the biochemical, electrophysiological, and behavioral consequences of this manipulation. These techniques will further elucidate the role of individual gene products in the complex behaviors associated with drug addiction. One major goal of this Core is to oversee the breeding, genotyping, and maintenance of all transgenic and knock out animals to be used by the individual Projects. This includes mice obtained from other laboratories as well as mice to be generated by this Core (see below). By centralizing these services, the Core will result in fewer animals being used for experimentation as well as considerable savings for money and investigator effort. A second major goal of this Core is to develop transgenic mice in which a transgene of interest can be induced in particular neuronal cell types in the brain. We have already succeeded in constructing such inducible,c ell- targeted transgenic mice by use of the tetracycline-regulated gene expression system. This work establishes the feasibility of this experimental approach, which will now be used to construct several new lines of mice required for the individual Projects of this grant. We also will use homologous recombination to generate additional mutant mice of interest to Project investigators. A third goal of this Core is to generate packaged viral particles to be used for viral-mediated gene transfer experiments in several of the Projects. We have demonstrated the ability of intra-cerebral injections of mutated herpes virus vectors to drive over-expression of proteins of interest in specific brain regions. This viral approach will complement the use of mutant mice to characterize the role of specific gene products in drug addiction.
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