This application is the competing renewal of a K02 Independent Scientist Career Development Award submitted by R. Christopher Pierce, Ph.D. The major goal of this K02 career development plan is to allow Dr. Pierce to continue to focus 75% effort to his primary research program. Dr. Pierce's research is currently supported by two NIDA R01s and focuses on animal models of cocaine craving and addiction. One of these awards (DA15214) aims to delineate the limbic circuitry underlying the reinstatement of cocaine-induced drug seeking, an animal model of relapse. Continuation of this K02 award will allow Dr. Pierce to expand the scope of these studies to include optogenetic modulation of neuronal activity in networks previously identified by his lab to regulate cocaine-induced behavioral plasticity. Optogenetics is an emerging technology that combines viral transfection of light-activated ion channels with laser light application via optic fiber. This technique allows for the reversible excitation or inhibition of neuronal activity on a millisecond timescale. The precise control afforded by optogenetic methods represents a perfect complement to ongoing pharmacological microinjection studies. Moreover, comparing and contrasting the effects of optogenetic manipulations to the effects of deep brain stimulation (DBS) will help illuminate the exact mechanism of action of DBS, which remains unclear. These optogenetic experiments will be performed in collaboration with Dr. Olivier Berton from the University of Pennsylvania (Penn) Psychiatry Department. Dr. Pierce's other R01 (DA22339) focuses on the biochemical mechanisms underlying dopamine-glutamate interactions in the nucleus accumbens shell that underlie the reinstatement of cocaine seeking. A complimentary methodology, patch clamp electrophysiology, will be added to ongoing work to allow for the examination of changes in AMPA glutamate receptor channel properties following cocaine self-administration. The proposed patch clamping experiments will be performed in collaboration with Dr. Gregory Carlson from the Penn Psychiatry Department. The release time from various administrative and teaching responsibilities over the past four years of K02 funding has been invaluable. The impact of the K02 award came to fruition in 2008, at which point newly formed research collaborations began to result in publications. In 2008, Dr. Pierce's research group co- authored two papers examining the role of AMPA receptor trafficking the reinstatement of cocaine seeking, which were published in Nature Neuroscience and Journal of Neuroscience. Dr. Pierce's team published another paper in Journal of Neuroscience in 2008 focusing on the ability of DBS to reduce cocaine craving in an animal model. Dr. Pierce's group has published 17 research and review articles since 2006. Continuation of this K02 award will allow Dr. Pierce to maintain 75% effort devoted to his existing research and also will facilitate the expansion of his research collaborations (as described above), which will have a significant positive impact on his research career development.
Cocaine addiction remains a major public health issue in the United Sates. The experiments described in this grant application are designed to delineate the neuronal circuitry as well as the neurochemical and biochemical mechanisms underlying an animal model of cocaine relapse. The overarching goal of this project is to identify novel therapeutic targets for cocaine craving and addiction.
|White, Samantha L; Vassoler, Fair M; Schmidt, Heath D et al. (2016) Enhanced anxiety in the male offspring of sires that self-administered cocaine. Addict Biol 21:802-10|
|White, Samantha L; Ortinski, Pavel I; Friedman, Shayna H et al. (2016) A Critical Role for the GluA1 Accessory Protein, SAP97, in Cocaine Seeking. Neuropsychopharmacology 41:736-50|
|Schmidt, H D; McFarland, K N; Darnell, S B et al. (2015) ADAR2-dependent GluA2 editing regulates cocaine seeking. Mol Psychiatry 20:1460-6|
|Ortinski, Pavel I; Briand, Lisa A; Pierce, R Christopher et al. (2015) Cocaine-seeking is associated with PKC-dependent reduction of excitatory signaling in accumbens shell D2 dopamine receptor-expressing neurons. Neuropharmacology 92:80-9|
|Guercio, Leonardo A; Schmidt, Heath D; Pierce, R Christopher (2015) Deep brain stimulation of the nucleus accumbens shell attenuates cue-induced reinstatement of both cocaine and sucrose seeking in rats. Behav Brain Res 281:125-30|
|Schmidt, Heath D; Kimmey, Blake A; Arreola, Adrian C et al. (2015) Group I metabotropic glutamate receptor-mediated activation of PKC gamma in the nucleus accumbens core promotes the reinstatement of cocaine seeking. Addict Biol 20:285-96|
|Ting, Jenhao H; Marks, David R; Schleidt, Stephanie S et al. (2014) Targeted gene mutation of E2F1 evokes age-dependent synaptic disruption and behavioral deficits. J Neurochem 129:850-63|
|Rasakham, Khampaseuth; Schmidt, Heath D; Kay, Kevin et al. (2014) Synapse density and dendritic complexity are reduced in the prefrontal cortex following seven days of forced abstinence from cocaine self-administration. PLoS One 9:e102524|
|Polter, Abigail M; Bishop, Rachel A; Briand, Lisa A et al. (2014) Poststress block of kappa opioid receptors rescues long-term potentiation of inhibitory synapses and prevents reinstatement of cocaine seeking. Biol Psychiatry 76:785-93|
|Vassoler, F M; Byrnes, E M; Pierce, R C (2014) The impact of exposure to addictive drugs on future generations: Physiological and behavioral effects. Neuropharmacology 76 Pt B:269-75|
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