This is an application for the renewal of a senior scientist research and mentorship award to provide protected time for Ken Mackie so he can achieve the following goals for his research, mentoring, and career development. Specific research objectives during the next five years include: (1) Obtaining a comprehensive understanding of the mechanisms of CB1 cannabinoid receptor desensitization, (2) Discerning the roles of endogenous and exogenous cannabinoids during two key neurodevelopmental stages (A) during embryonic life and (B) during the adolescent maturation of the prefrontal cortex, (3) Exploring the therapeutic potential of CB2 cannabinoid receptor functional selectivity in making more effective analgesics and in attenuating cocaine reward, (4) Using simplified experimental systems (primarily cultured autaptic neurons) to address significant, outstanding issues in endocannabinoid-mediated synaptic plasticity. Dr. Mackie's mentoring will focus on mentoring four groups of scientists that encompass the full career spectrum: undergraduates at Indiana University, graduate and medical students at Indiana University, post-doctoral fellows, and junior faculty. His career development will emphasize the incorporation of more powerful imaging, informatic, proteomic, and behavioral tools into his research, as well as continuing to be heavily committed to service (editorial duties, meeting organization, and grant reviews) related to drug abuse research.
This application for a Senior Scientist Research and Mentorship Award seeks protected time for Ken Mackie, MD so that he may pursue research into the mechanisms of action of cannabis and endogenous cannabinoids and the consequence of their regular use. In the process of this he will also be mentoring students and faculty as they become drug abuse researchers.
|Mitjavila, Jose; Yin, Danielle; Kulkarni, Pushkar M et al. (2018) Enantiomer-specific positive allosteric modulation of CB1 signaling in autaptic hippocampal neurons. Pharmacol Res 129:475-481|
|Sepers, Marja D; Smith-Dijak, Amy; LeDue, Jeff et al. (2018) Endocannabinoid-Specific Impairment in Synaptic Plasticity in Striatum of Huntington's Disease Mouse Model. J Neurosci 38:544-554|
|Chen, Yi-Hung; Lee, Hsin-Jung; Lee, Ming Tatt et al. (2018) Median nerve stimulation induces analgesia via orexin-initiated endocannabinoid disinhibition in the periaqueductal gray. Proc Natl Acad Sci U S A 115:E10720-E10729|
|Hermes, Douglas J; Xu, Changqing; Poklis, Justin L et al. (2018) Neuroprotective effects of fatty acid amide hydrolase catabolic enzyme inhibition in a HIV-1 Tat model of neuroAIDS. Neuropharmacology 141:55-65|
|Kasten, Chelsea R; Zhang, Yanping; Mackie, Ken et al. (2018) Short-Term Genetic Selection for Adolescent Locomotor Sensitivity to Delta9-Tetrahydrocannabinol (THC). Behav Genet 48:224-235|
|Lin, Xiaoyan; Dhopeshwarkar, Amey S; Huibregtse, Megan et al. (2018) Slowly Signaling G Protein-Biased CB2 Cannabinoid Receptor Agonist LY2828360 Suppresses Neuropathic Pain with Sustained Efficacy and Attenuates Morphine Tolerance and Dependence. Mol Pharmacol 93:49-62|
|Leishman, Emma; Manchanda, Meera; Thelen, Rachel et al. (2018) Cannabidiol's Upregulation of N-acyl Ethanolamines in the Central Nervous System Requires N-acyl Phosphatidyl Ethanolamine-Specific Phospholipase D. Cannabis Cannabinoid Res 3:228-241|
|Straiker, Alex; Dvorakova, Michaela; Zimmowitch, Anaelle et al. (2018) Cannabidiol Inhibits Endocannabinoid Signaling in Autaptic Hippocampal Neurons. Mol Pharmacol 94:743-748|
|Slivicki, Richard A; Xu, Zhili; Kulkarni, Pushkar M et al. (2018) Positive Allosteric Modulation of Cannabinoid Receptor Type 1 Suppresses Pathological Pain Without Producing Tolerance or Dependence. Biol Psychiatry 84:722-733|
|Shonesy, Brian C; Parrish, Walker P; Haddad, Hala K et al. (2018) Role of Striatal Direct Pathway 2-Arachidonoylglycerol Signaling in Sociability and Repetitive Behavior. Biol Psychiatry 84:304-315|
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