The introduction of gene targeting to the study of brain function has rapidly advanced our knowledge of how various neurotransmitters, receptors and effectors are involved in basic aspects of brain function. However, there are few sophisticated behavioral models that can be used to establish the roles of various gene products in the addiction process. We propose to develop three distinct behavior models to apply to the study of drug addiction and to extend such models specifically for use in genetically altered mice. We also propose to begin an extensive series of studies to determine the feasibility of forward genetic approaches to identify genes involved in cocaine addiction. The first model utilizes a novel signaled switching task from a schedule that reinforces high-rate responding to a schedule that reinforces low-rate responding. An FR-8 evaluates behavioral activation whereas the DRL-90 evaluates working memory, response inhibition and impulsivity. The second model is one that assesses aspects of behavior indicative of withdrawal from repeated cocaine exposure. We have found that """"""""binge-type"""""""" administration of cocaine for several consecutive days leads not only to locomotor sensitization upon cocaine challenge, but also to profound nocturnal hypoactivity during the first several days of cocaine abstinence. The third model will utilize cocaine self-administration coupled to a variant of the extinction/reinstatement model of drug seeking behavior. In addition to the successful use of transgenic approaches to identify how genes are related to particular functions, the use of forward genetics (proceeding from phenotype to gene) has also been tremendously useful. To use this approach one must have a rapid high throughput screen for mutations of interest. We propose to test the possibility of using two rapid high throughput screens as possible determinants of mutations altering sensitivity to cocaine. The development of these models should allow phenotypic characterization of behaviors related to drug taking and drug seeking and provide novel tests for various transgenic mice.
