Behavior Consequences of Amphetamine Dependence in Mice

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DESCRIPTION (provided by applicant): Drug abuse and dependence continue to be a major health and social problem in the United States. Early laboratory research on drug abuse has focused on the directly rewarding (euphoria) or aversive (withdrawal symptoms) consequences of abused drugs to explain persistent illegal drug use. In response to consistent clinical reports of "drug craving", laboratory researchers have also examined the direct effects that abused drugs have on basic reward and associative systems of the brain. However, tolerance to euphoria, withdrawal symptoms, or craving is not necessary or sufficient to the psychiatric definition of Substance Abuse or Dependence. Review of the "Diagnostic and Statistical Manual of Mental Disorders" shows that a prominent feature of these syndromes is the disruption of school, work, and/or social (personal and/or legal) behaviors. This disruption of alternative behaviors is thought to occur as a reorganization of priorities in response to a more rewarding and compulsion-inducing drug. Behavioral sensitization research has shown that addictive drugs can change dopamine (DA) and other neurotransmitter systems. Other research has shown that some of these same DA systems mediate not only drug reward, but also anticipatory and conditioned behavior for other natural rewards (food, sex, and avoidance of harm). The purpose of this proposal is to develop a mouse behavioral model of the effects of chronic intermittent drug exposure on working for rewards. Aim 1 will determine if working for a reward in a non-drug environment will be changed by intermittent repeated amphetamine (AMPH) in a separate distinct environment in C57BL/6J mice. Aim 2 will determine if these indirect effects persist after AMPH ceases. After AMPH sensitization and withdrawal in the drug-related environment, Aim 3 will determine if low doses of AMPH in the previous work environment will augment responding differently for sensitized versus unsensitized C57BL/6J mice. The ultimate goal of these experiments is to generate an animal model of the transition from substance exposure to Substance Dependence in a species that will allow for multi-level approaches (behavioral, pharmacological and genetic) to the discovery of mechanisms that contribute to the development of drug dependence.