Nucleus accumbens synaptic mechanisms of opiate reward and aversion

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DESCRIPTION: My career goal is to obtain an independent academic position at a respected research university, studying the effects of opiates on striatal synaptic function and behavior, and training future scientists in this area. I developed a passionate interest in this topic during my doctoral studies at the University of Minnesota, where I used behavioral pharmacology to investigate the rewarding and aversive properties of abused drugs, and studied how drug exposure affects synaptic function in the nucleus accumbens (NAc). As a postdoctoral scholar at Stanford University, I have worked with Drs. Robert Malenka and Thomas Sudhof to develop and expand my training in the molecular basis of NAc circuit function. A primary goal of this career development award is to obtain additional training in optogenetic approaches to studying NAc circuitry that will help launch my independent career. My career development in addiction research and training in optogenetics will be supervised by Dr. Malenka at Stanford, with additional support from Dr. Sudhof and Dr. Karl Deisseroth. I will learn to perform optogenetic stimulation of specific NAc synaptic connections in brain slice preparations, while performing whole-cell recordings from identified subtypes of NAc medium spiny neurons, allowing precise definition of synaptic connections based on presynaptic source and postsynaptic target. I will also learn to stimulate specific NAc circuit elements in vivo to examine the impact on behavioral responses. During the mentored phase of this award, I will focus on the synaptic mechanisms of morphine reward, as well as synaptic modifications of NAc circuitry caused by chronic intermittent morphine exposure. During the independent phase of this award, I will extend this analysis to chronic continuous opiate administration, and examine the synaptic and behavioral consequences of opiate withdrawal using optogenetic approaches. My training and career development in opioid pharmacology will be facilitated by an Advisory Committee of established researchers in this area, who will be involved in both the mentored and independent phases of this award. Significant components of this proposal include parallel study of the same NAc circuit elements in opiate reward and aversion, as well as direct and controlled comparison of intermittent and continuous opiate exposure. These different temporal patterns of opiate administration are associated with distinct neurobiological, behavioral, and clinical outcomes. These experiments will lay the groundwork for future grant applications focused on the molecular mechanisms of opiate effects on NAc circuitry. I hope that my research in this area will benefit public health by guiding efforts to reduce abuse of prescription painkillers.