CURRENT PROJECTS

Adenosinergic Signaling in Alcoholism and Drug Abuse:

Striatal CREB activation is associated with reduced drug reward, and our studies demonstrate increased glutamate-driven CREB activation in the striatum of ENT1 null mice. This appears to result from diminished activation of striatal adenosine A1 receptors. We will examine the role of CREB signaling in regulating behavioral responses to alcohol in ENT1 null mice. We plan to investigate the possible compensatory mechanism which results in reduced adenosine concentration in ventral striatum. For this study, we will examine expression and activity of other transporters or enzymes including ENT2, CNT1, CNT2, adenosine deaminase and adenosine kinase. The primary goal of this project is to understand signaling pathways underlying enhanced alcohol drinking behavior in ENT1 null mice that may be important in alcoholism and drug abuse in general.

Target Validation through Behavioral Pharmacology:

We will validate the pharmacological agents found to be effective in signaling studies through behavioral assays. For ENT1 null mice, we will examine the compounds that reduce CREB function in ENT1 null mice, and determine whether they will also normalize ethanol reward and alcohol consumption in ENT1 null mice. These studies will also allow me to correlate pharmacological manipulations of CREB phosphorylation in the above goals with behavioral assays of alcohol reward and consumption. For this experiment, we will first microinject drugs into the nucleus accumbens to assess their effects in that specific brain region. Drugs that cross the blood-brain barrier will also be administered by intraperitoneal injection (i.p.) to test if they are effective when given systemically, since this could be of clinical importance. To confirm whether basal increases in CREB activity are associated with increased expression of CRE-regulated genes, we will focus on two CRE-mediated genes, enkephalin and dynorphin, which are opioid peptides thought to be important in the rewarding (enkephalin) and aversive (dynorphin) actions of abused drugs including alcohol.