Research Interests
Our laboratory studies the behavioral consequences of dopamine D2 supersensitization, a phenomenon known as D2 receptor priming. The dopamine D2 receptor is primed through neonatal quinpirole (a dopamine D2/D3 agonist) treatment during the first 3-4 weeks of life in a rat. Essentially, priming of the D2 receptor increases the sensitivity of this receptor, which is relevant to several clinical conditions including schizophrenia, attention-deficit hyperactivity disorder (ADHD), obsessive-compulsive disorder (OCD), and bipolar disorder, not to mention the long-term effects of drug abuse. We have found that neonatal quinpirole treatment produces a number of performance deficits in cognitive, motor, and sensory tasks, results in significant decreases of choline acetyltransferase (ChAT), nerve growth factor (NGF), brain-derived nerve growth factor (BDNF) in brain areas that are important in addiction (nucleus accumbens) and cognition (hippocampus). One of our most prominent findings has been that acute or chronic amphetamine (street name: speed) results in a robust 4-5 fold increase in dopamine release in the nucleus accumbens of D2 receptor-primed rats as compared to non D2 receptor-primed rats that have received amphetamine. Behaviorally, amphetamine produces a significant increase in the locomotor response in these animals as well, and this effect, somewhat surprisingly, is more prominent in males as compared to females. This particular project is funded by the National Institute on Drug Abuse (NIDA) on an R15 grant mechanism (R15DA020481-01A1). Recently, in collaboration with our colleagues at Vanderbilt, we have shown that neonatal quinpirole treatment results in significant decreased expression of a regulator of G-protein signaling (RGS), RGS9, in the frontal cortex, nucleus accumbens, and striatum. RGS9 co-localizes with dopamine D2 receptors, and this finding is consistent with post-mortem findings in schizophrenics.
A new secondary line of research involves studying the social defeat stress model in the mouse. Past findings have shown that this model has clinical relevance towards depression, as social defeat can be alleviated by chronic antidepressant treatment. In a recent clinical study, results have shown that the sleep aid, Lunesta (eszopiclone) facilitates the antidepressant action of Prozac (fluoxetine) in depressed patients. Sepracor Pharmaceuticals is currently funding a project in our laboratory to further analyze the interaction of eszopiclone and fluoxetine in a mouse model of social defeat, and the aim is to alleviate social defeat stress in the mouse, as well as analyze neurochemical mechanisms of this effect. This project is in collaboration with Dr. Greg Ordway, chair of Pharmacology in the Quillen College of Medicine here at ETSU.