Drug addiction is a major detriment to public health in today's society, with lifelong effects on people who use illicit drugs and their families. One of the most vexing problems with drugs of abuse is that addicts have a tremendous propensity to relapse, even with proper treatment. In animal models, one of the most consistent findings after prolonged drug administration is an increase in the number of dendritic spines in specific regions of the brain. These structural changes remain even after long periods of withdrawal. In our lab, we work on a protein, Kalirin-7, that has been implicated in the formation and maintenance of dendritic spines. It is our hypothesis that this increase in dendritic spines plays a role in the long-term effects of drug abuse, and that Kalirin-7 is an essential player in the structural changes. We will be using a line of mice genetically deficient in Kalirin-7 (Kal7KO) to determine if their behavioral or biochemical response to cocaine is different from that of wildtype mice. Initial studies have shown that the Kal7KO mice are hypersensitive to the locomotor sensitization effects of cocaine, yet show decreased place preference for cocaine. We are now trying to clarify the specific pathways that Kalirin-7 modulates by combining place preference for cocaine with co-administration of receptor antagonists (Aim 1). Interestingly, when using a cocaine dosing regimen that increases dendritic spines in the nucleus accumbens of Wt animals, Kal7KO animals do not show an increase in dendritic spines. Moving forward, we will be using mice expressing GFP driven by the dopamine 1 receptor promoter to examine the expression and morphological effect of Kal7 in specific subsets of striatal neurons (Aim 2). The different populations of neurons in the striatum play different roles in the addiction process, and understanding of their function is critical for the understanding of addiction. Additionally, we have recently discovered that Kal7KO animals have altered surface trafficking of the NR2B subunit of NMDA receptors. Proper function of NMDA receptors is essential for the normal plasticity underlying learning and memory, and altered NMDA receptor function has been shown to play a role in the development of drug addiction. Using both cell culture models and tissue from cocaine treated animals we are now investigating the specific interaction between Kalirin-7 and NR2B, and how Kalirin-7 alters the localization and trafficking of this critical receptor (Aim 3). When these studies are finished, we hope to have greatly expanded the knowledge of the roles that alterations in neuronal morphology and receptor trafficking play in the pathophysiology of drug addiction.

Public Health Relevance

Drug addiction is a major problem that every year costs the lives of many people, and takes an immeasurable financial and emotional toll on families around the country. While the underlying causes of addiction are not well understood, it is known that there are long-standing changes in the neuronal structure of addicted patients. We study a protein, Kalirin-7, that is essential in the control of neuronal structure, and are now focusing on how its ability to change the shape of neurons may alter the course of addiction.

Agency
National Institute of Health (NIH)
Institute
National Institute on Drug Abuse (NIDA)
Type
Individual Predoctoral NRSA for M.D./Ph.D. Fellowships (ADAMHA) (F30)
Project #
5F30DA026706-02
Application #
8352102
Study Section
Special Emphasis Panel (ZRG1-F02A-J (20))
Program Officer
Avila, Albert
Project Start
2010-12-15
Project End
2013-12-14
Budget Start
2011-12-15
Budget End
2012-12-14
Support Year
2
Fiscal Year
2012
Total Cost
$44,865
Indirect Cost
Name
University of Connecticut
Department
Neurosciences
Type
Schools of Medicine
DUNS #
022254226
City
Farmington
State
CT
Country
United States
Zip Code
06030
Kiraly, Drew D; Nemirovsky, Natali E; LaRese, Taylor P et al. (2013) Constitutive knockout of kalirin-7 leads to increased rates of cocaine self-administration. Mol Pharmacol 84:582-90
Kiraly, Drew D; Lemtiri-Chlieh, Fouad; Levine, Eric S et al. (2011) Kalirin binds the NR2B subunit of the NMDA receptor, altering its synaptic localization and function. J Neurosci 31:12554-65
Eipper-Mains, Jodi E; Kiraly, Drew D; Palakodeti, Dasaradhi et al. (2011) microRNA-Seq reveals cocaine-regulated expression of striatal microRNAs. RNA 17:1529-43
Kiraly, Drew D; Stone, Kathy L; Colangelo, Chris M et al. (2011) Identification of kalirin-7 as a potential post-synaptic density signaling hub. J Proteome Res 10:2828-41