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.

Public Health Relevance

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.

National Institute of Health (NIH)
National Institute on Drug Abuse (NIDA)
Research Scientist Award (K05)
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Study Section
Molecular Neuropharmacology and Signaling Study Section (MNPS)
Program Officer
Pollock, Jonathan D
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Indiana University Bloomington
Schools of Arts and Sciences
United States
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Delgado-Peraza, Francheska; Ahn, Kwang H; Nogueras-Ortiz, Carlos et al. (2016) Mechanisms of Biased β-Arrestin-Mediated Signaling Downstream from the Cannabinoid 1 Receptor. Mol Pharmacol 89:618-29
Tung, Li-Wei; Lu, Guan-Ling; Lee, Yen-Hsien et al. (2016) Orexins contribute to restraint stress-induced cocaine relapse by endocannabinoid-mediated disinhibition of dopaminergic neurons. Nat Commun 7:12199
Xu, Changqing; Hermes, Douglas J; Mackie, Ken et al. (2016) Cannabinoids Occlude the HIV-1 Tat-Induced Decrease in GABAergic Neurotransmission in Prefrontal Cortex Slices. J Neuroimmune Pharmacol 11:316-31
Murataeva, Natalia; Dhopeshwarkar, Amey; Yin, Danielle et al. (2016) Where's my entourage? The curious case of 2-oleoylglycerol, 2-linolenoylglycerol, and 2-palmitoylglycerol. Pharmacol Res 110:173-80
Dhopeshwarkar, Amey; Mackie, Ken (2016) Functional Selectivity of CB2 Cannabinoid Receptor Ligands at a Canonical and Noncanonical Pathway. J Pharmacol Exp Ther 358:342-51
Lu, Hui-Chen; Mackie, Ken (2016) An Introduction to the Endogenous Cannabinoid System. Biol Psychiatry 79:516-25
Leishman, Emma; Mackie, Ken; Luquet, Serge et al. (2016) Lipidomics profile of a NAPE-PLD KO mouse provides evidence of a broader role of this enzyme in lipid metabolism in the brain. Biochim Biophys Acta 1861:491-500
Leishman, Emma; Cornett, Ben; Spork, Karl et al. (2016) Broad impact of deleting endogenous cannabinoid hydrolyzing enzymes and the CB1 cannabinoid receptor on the endogenous cannabinoid-related lipidome in eight regions of the mouse brain. Pharmacol Res 110:159-72
Marcus, David J; Zee, Michael; Hughes, Alex et al. (2015) Tolerance to the antinociceptive effects of chronic morphine requires c-Jun N-terminal kinase. Mol Pain 11:34
Bashashati, M; Nasser, Y; Keenan, C M et al. (2015) Inhibiting endocannabinoid biosynthesis: a novel approach to the treatment of constipation. Br J Pharmacol 172:3099-111

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