Many previous studies have identified neuroadaptations to cocaine treatment such as changes in the content of the post synaptic density, actin cycling, spine morphology and behavior that may contribute to the long lasting craving associated with cocaine addiction. Recently, there has been a renewed interest in the role of the extracellular matrix (ECM) and its receptors on these adaptations in drug addiction as well as other well studied areas involving neuroplasticity. In other fields of interest, beta integrins, which are transmembrane bidirectional ECM receptors, have been shown to regulate actin polymerization, glutamate receptor surface expression and function in the post synaptic density, spine morphology in response to stimulation and behavior. This proposal will be the first to directly address the role of beta integrins in the neuroadaptations due to cocaine use and relapse. Preliminary studies described show that beta integrins are altered after withdrawal from chronic cocaine treatment and have piqued interest in the changes in protein expression after self administration and whether altering the function or expression of integrins modulates the function of PSD proteins and ultimately effects reinstatement of drug seeking behavior.
Specific aim 1 will replicate our findings in the non contingent model in extinguished self administered rats by Western blot analysis.
Specific aim 2 will address whether alteration of the function of integrins by activating signaling via an activating protein or knocking down beta 1 integrin expression virally with siRNA will alter the expression of other relapse related post synaptic protein.
Specific aim 3 will investigate whether modulating the activation or expression of beta integrins will affect drug seeking behavior in the reinstatement model. Completion of these aims will elucidate the role of beta integrins in the expression of cocaine induced neuroadaptations that may lead relapse. According to the National Survey on Drug Use and Health, over 5 million people reporting using cocaine annually in 2004. This population has since increased and continues to affect family structure, public safety and our economy. If successful these experiments and subsequent publications may suggest new targets for therapy for individuals plagued by cocaine addiction. ? ? ?
| Wiggins, Armina T; Pacchioni, Alejandra M; Kalivas, Peter W (2009) Integrin expression is altered after acute and chronic cocaine. Neurosci Lett 450:321-3 |
