The current application for a five-year mentored Career Development Award (K01) submitted by Dr. Pavel Ortinski proposes acquisition of training in the behavioral pharmacology of drug abuse. Specifically, the requested training will examine the role of D1-like dopamine and NMDA receptor interaction in an animal model of cocaine self-administration and reinstatement of cocaine seeking. This training will facilitate thedevelopment of an independent research program focused on the analysis of synaptic mechanisms of cocaine seeking and relapse. The research will be conducted at the University of Pennsylvania under the mentorship of Dr. Chris Pierce. Candidate: Dr. Ortinski has demonstrated a record of research projects implementing the analyses of synaptic function and physiology in several experimental models. His Ph.D. thesis, completed at Georgetown University under the mentorship of Dr. Stefano Vicini, used electrophysiological patch-clamp recordings in cell cultures and brain slices to investigate the regulation of inhibitory synaptic strength by GABA-A receptor subtypes. Dr. Ortinski then completed a two-year postdoctoral fellowship with Dr. Douglas Coulter at the Children's Hospital of Philadelphia/University of Pennsylvania where he evaluated contributions of the astrocytic glutamate/glutamine metabolic pathway to inhibitory control over hippocampal network activity in epilepsy. These graduate and post-graduate experiences resulted in three first-author primary research and eight co-authored/review publications in peer-reviewed journals. In search of opportunities to integrate his synaptic physiology experience into a broader context of behavioral-level studies, Dr. Ortinski had a series of meetings with Dr. Chris Pierce at the UPenn School of Medicine. Seeing a relative shortage of synaptic function analyses in cocaine abuse research and realizing this represented a chance to establish an independent line of synaptic physiology research with significant potential impact, Dr. Ortinski joined Dr. Pierce's laboratory as a Research Associate. In the short time since his appointment, Dr. Ortinski has assembled a set-up for electrophysiological recordings from brain slices and used it to acquire (with Dr. Pierce's guidance) a considerable amount of data extending a series of recent findings from the Pierce lab. Environment: The basic addiction research community at UPenn, affiliated local centers, and nearby universities is very prominent and creates a reservoir of expertise for consultation and collaboration. There are ample opportunities for scientific interactions at meetings and seminars organized by various departments within UPenn's vibrant neuroscience community. Additionally, several campus offices developed programs in career and research skill training for biomedical faculty at the postdoctoral level. All of these establish an extensive resource-rich environment for successful research and career development. Research: The research proposed in this application builds upon substantial evidence that interactions between dopamine and glutamate systems in the nucleus accumbens mediate important aspects of drug-seeking and drug-taking behaviors. For example, several laboratories, including that of Dr. Pierce, have demonstrated that activation of D1-like dopamine receptors in the nucleus accumbens reinstates cocaine seeking, in part, by increasing the trafficking of GluA1 subunit-containing AMPA receptors to synapses in this brain region. In contrast to studies of neuronal plasticity throughout the brain, however, the involvement of NMDA receptors in cocaine-induced neuronal plasticity has not been assessed systematically. My preliminary results show that, relative to control animals, transient stimulation of D1-like dopamine receptors (as occurs during cocaine self-administration) in cocaine-experienced animals elicits a long-lasting increase of currents mediated by NMDA receptors in the medium spiny neurons of the nucleus accumbens shell. NMDA receptors are known to be involved in reinstatement of cocaine-seeking. Thus, it is proposed that regulation of NMDA receptor function by D1-like receptors in the nucleus accumbens shell contributes significantly to persistent cocaine-seeking behaviors. Career development plan: A range of activities combining coursework, conference and workshop attendance, formal research presentations, hands-on training and teaching is proposed. Formal coursework will consist of a Statistical Methods and Data Analysis for Biostatistics graduate students course and a graduate Neuropsychopharmacology course. Two research conferences a year will be attended: an annual meeting of the Society for Neuroscience and either a meeting of the College of Problems on Drug Dependence or a Gordon conference on Excitatory Synapses and Brain Function. Two to three formal presentations of research yearly are proposed at various venues. Biomedical career skills training will be acquired through attendance of workshops and seminars. Hands-on training will be acquired in the course of the proposed research. Teaching plans include lectures in several graduate-level neuroscience courses. The overall goal of the career development plan is to facilitate the integration of behavioral pharmacology and neuronal physiology approaches in the proposed research and to establish a foundation of skills necessary for a successful independent career in addiction research.
Cocaine abuse is a major public health problem in the United States that remains without an effective therapeutic treatment. This project examines how a main target of cocaine action in the brain (the mesoaccumbal dopamine system) interacts with another prominent component of brain signaling (NMDA receptors) and the consequences of this interaction on addictive behavior in an animal model of human cocaine abuse. Increased understanding of the link between the brain targets of cocaine action and addictive behavior is expected to help develop novel therapies for cocaine abuse and relapse.
|Zhou, Luyi; Fisher, Miranda L; Cole, Robert D et al. (2018) Neuregulin 3 Signaling Mediates Nicotine-Dependent Synaptic Plasticity in the Orbitofrontal Cortex and Cognition. Neuropsychopharmacology 43:1343-1354|
|Galloway, Ashley; Adeluyi, Adewale; O'Donovan, Bernadette et al. (2018) Dopamine Triggers CTCF-Dependent Morphological and Genomic Remodeling of Astrocytes. J Neurosci 38:4846-4858|
|Hernandez, Nicole S; O'Donovan, Bernadette; Ortinski, Pavel I et al. (2017) Activation of glucagon-like peptide-1 receptors in the nucleus accumbens attenuates cocaine seeking in rats. Addict Biol :|
|Ortinski, Pavel I; O'Donovan, Bernadette; Dong, Xiaoyu et al. (2017) Integrase-Deficient Lentiviral Vector as an All-in-One Platform for Highly Efficient CRISPR/Cas9-Mediated Gene Editing. Mol Ther Methods Clin Dev 5:153-164|
|Zhou, Luyi; Andersen, Haley; Arreola, Adrian C et al. (2016) Behavioral History of Withdrawal Influences Regulation of Cocaine Seeking by Glutamate Re-Uptake. PLoS One 11:e0163784|
|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|
|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|
|Tatard-Leitman, Valerie M; Jutzeler, Catherine R; Suh, Jimmy et al. (2015) Pyramidal cell selective ablation of N-methyl-D-aspartate receptor 1 causes increase in cellular and network excitability. Biol Psychiatry 77:556-68|
|Briand, Lisa A; Kimmey, Blake A; Ortinski, Pavel I et al. (2014) Disruption of glutamate receptor-interacting protein in nucleus accumbens enhances vulnerability to cocaine relapse. Neuropsychopharmacology 39:759-69|
|Ortinski, Pavel I (2014) Cocaine-induced changes in NMDA receptor signaling. Mol Neurobiol 50:494-506|
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