Long-term changes in the cellular properties of neurons are known to be part of the mechanisms mediating both continued drug abuse and relapse in individuals who have been abstinent from drug use. However, this leaves open the question of what leads to the initiation and maintenance of drug use prior to the induction of sensitization from repeated drug use? One component of the answer to this question might lie in an individual's life history or prior experiences. Like drugs of abuse, expression of motivated behaviors will activate the mesocorticolimbic dopamine system. It would be of great importance to delineate the cellular processes related to neural plasticity following experience with motivated behaviors (e.g., sexual behavior). We discovered that prior sexual experience sensitizes the dopamine response to sexual interactions and also produces behavioral sensitization to the initial presentation of amphetamine in otherwise drug-naive animals. This latter process, termed 'cross-sensitization', is fundamental to understanding how an animal's life history can contribute to a predisposition to drug abuse. Because so little is known about the cellular mechanisms altered by experience in animals engaging in motivated behaviors, the long-term goal of this project is to compare at the cellular level the degree to which motivated behaviors and drugs of abuse have common (or discrepant) mechanisms of sensitization of dopamine pathways. There are three specific aims to this project. The first aim will identify changes in proteins involved in dendritic remodeling as a function of sexual experience. The second aim will pharmacologically dissect signaling pathways that underlie behavioral and neural morphological responses to sexual experience. The final aim will pharmacologically identify signaling pathways key to the cross-sensitization of sexual experience to amphetamine-induced locomotor behavior. The experiments in this proposal are designed to distinguish those cellular pathways that mediate drug sensitization to the exclusion of sensitization processes important for normal motivated behaviors. The degree to which there are shared anatomical loci and cellular mechanisms between normal motivated behaviors and drug abuse will provide insight into risk factors for the initiation of drug use in humans and for the development of therapies for the treatment of addiction.