Unconditioned locomotor behavior has been used widely as a behavioral probe to examine the functional integrity of neural systems that are critically involved in the initiation or maintenance of drug-taking behavior. Typically, the amount of locomotor behavior provides an index of general arousal and is used to examine whether drugs have stimulant properties. However, unconditioned locomotor behavior reflects a complex set of behavioral processes that include approach/avoidance, spatial mapping, novelty seeking, and exploratory behaviors. The goal of this proposal is to extend this approach to the study of mouse behavior in order to answer the following central question: Can unconditioned locomotor behavior in mice be used to extract multidimensional behavioral profiles that are reliable and have predictive validity for underlying behavioral constructs, molecular substrates, and pharmacological effects of drugs of abuse? The validity and utility of this approach will be examined by comparing the behavioral profiles of both male and female C57BI/6J and l29SvJ mice in a test-retest design and after administration of methamphetamine or MDMA. In rats, methamphetamine increases locomotor activity and exploratory behavior, has no effect on the geometric patterns of behavior but increases the unpredictability of movement sequences. In contrast, although MDMA also increases locomotor activity, it decreases exploratory behavior and induces a perseverative movement pattern in rats. It is hypothesized that independent of the predicted trait-related differences in the behavioral profiles of the two strains of mice similar drug-specific behavioral profiles will be evident in mice.
The specific aims are: 1. To establish the reliability and predictive validity of measures characterizing the behavioral profile of unconditioned locomotor behavior in mice in analogy to previously established behavioral profiles in rats. 2. To determine whether methamphetamine and MDMA predictably and reliably affect the behavioral profiles of unconditioned locomotor behavior in mice in analogy to previously established behavioral profiles induced by these drugs in rats. 3. To determine whether paradigmatic and pharmacological manipulations that affect approach/avoidance predictably change the baseline behavioral profile and the changes in the behavioral profile induced by methamphetamine and MDMA. The results from these studies will provide a set of measures derived from a widely used behavioral paradigm to examine the molecular basis of the effects of drugs of abuse using genetically modified mice.
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