Drug addiction is a worldwide problem that affects every class of society, costing the United States over 400 billion dollars a year. Currently, the main treatments for addiction are focused on the cellular mechanisms of the drug's action and/or drug substitution. However, this does not address the long-term neurobiological adaptations that result from drugs of abuse. Specifically, neural plasticity may be important in mediating the long-term behavioral effects of drugs of abuse, even after cessation of drug use. It seems that drugs of abuse and natural motivated behaviors operate via similar cellular mechanisms, and therefore looking at the drug literature is beneficial in identifying potential cellular processes underlying natural motivated behaviors. The transcription factor deltaFosB, an alternative splice variant of FosB, accumulates following chronic exposure to drugs of abuse and may be important in mediating the long term behavioral and molecular effects of drugs of abuse. This proposal is aimed at elucidating whether deltaFosB is a molecular component in natural motivated behaviors, such as sexual behavior. Similar to drugs of abuse, sexual experience activates the mesocorticolimbic dopamine system, which can result in both behavioral and cellular plasticity. By using sexual behavior as a model to study behavioral and neural plasticity, there can be comparisons between completely naive animals and differentially experienced animals. There are two specific aims in this proposal.
The first aim will analyze whether the knockdown of deltaFosB mediated transcription, by overexpressing the dominant negative modulator deltaJunD, in the nucleus accumbens will eliminate the reward associated with sexual experience. The goal of the second aim is to study the differential expression of deltaFosB and its downstream transcription effects in a limbic circuit following sexual experience. Unique to our model of motivated behavior is the implication that an animal's past experience can sensitize the mesocorticolimbic dopamine pathway, and perhaps contribute to the susceptibility of a drug naive animal to addiction. By elucidating the mostly unknown mechanisms that underlie natural motivated behaviors, a molecular pharmacological target differentially affecting the abnormal long-term plasticity specific to drugs of abuse can be identified. My ultimate career goal is to be an independent researcher at a small university where I will be in close contact with student researchers. I feel that this position would allow me to continue my research while also instructing undergraduates in research techniques, and hopefully inspire students to pursue research career paths. The training that I will receive from an NRSA will provide the necessary preparation that I will need to meet my career goals. I will specifically perfect my immunohistochemistry, Western blotting, surgery, and behavioral testing skills as well as learning new techniques, such as PCR. This PCR training will further broaden the array of technical training that will ultimately make me a more effective researcher. I plan on taking advantage of an NRSA award by supplementing my training and learning new skills while submerged in an academic environment with numerous resources. In addition, my role as the primary undergraduate research supervisor in our laboratory will hone my instructive and lab management skills.
| Klingerman, Candice M; Patel, Anand; Hedges, Valerie L et al. (2011) Food restriction dissociates sexual motivation, sexual performance, and the rewarding consequences of copulation in female Syrian hamsters. Behav Brain Res 223:356-70 |
| Hedges, Valerie L; Staffend, Nancy A; Meisel, Robert L (2010) Neural mechanisms of reproduction in females as a predisposing factor for drug addiction. Front Neuroendocrinol 31:217-31 |
