This is an application for a NIDA senior scientist award. The primary goal of my research is to understand the mechanisms underlying the acute and chronic effects of cannabinoids (the principal psychoactive constituents of cannabis). My studies are focused on the function and regulation of the CB1 (neuronal) and CB2 (""""""""peripheral"""""""") cannabinoid receptors. Cannabinoids, acting at CB1 receptors are potent modulators of ion channel function. Consistent with these actions, efficacious cannabinoids decrease neuronal excitability and inhibit neurotransmitter release. Interestingly, endogenous cannabinoids acting via CB1 receptors inhibit neurotransmission and mediate several forms of short and long-term neuronal plasticity-in part through non-ion channel signaling pathways. CB2 receptors, whose activation is devoid of apparent psychoactivity, have recently been shown to be involved in processes as diverse as analgesia, bone growth, and atherosclerosis, and are receiving intense scrutiny as potential therapeutic targets. Over the next five years we will continue our studies at the molecular and genetic level, emphasizing the following specific aims. Is behavioral tolerance to cannabinoids due to CB1 receptor phosphorylation? Is it possible to identify CB1 and CB2 agonists that cause little desensitization? What role does dimerization have in the signaling of CB1 and CB2 receptors? What are the determinants of the speed of CB1 receptor signaling? What is the role of GPR55, a third cannabinoid receptor, in cannabinoid action? Accomplishing these goals will significantly advance our understanding of the cellular actions of cannabinoids. To accomplish these ambitious goals I have assembled a group of collaborators and consultants whose expertise complements that currently in place in my laboratory. Three facts underscore the importance of having a solid understanding of cannabinoid receptor function at the molecular level. 1. Chronic cannabis use is a significant social issue. 2. We need a firm understanding of the cellular effects of cannabinoid receptor activation to interpret the possible benefits of their therapeutic manipulation. 3. We know little about the physiological role of endogenous cannabinoids in healthy or diseased tissues.

Agency
National Institute of Health (NIH)
Institute
National Institute on Drug Abuse (NIDA)
Type
Research Scientist Award (K05)
Project #
5K05DA021696-04
Application #
7840552
Study Section
Human Development Research Subcommittee (NIDA)
Program Officer
Pollock, Jonathan D
Project Start
2007-06-05
Project End
2012-05-31
Budget Start
2010-06-01
Budget End
2011-05-31
Support Year
4
Fiscal Year
2010
Total Cost
$129,597
Indirect Cost
Name
Indiana University Bloomington
Department
Psychology
Type
Schools of Arts and Sciences
DUNS #
006046700
City
Bloomington
State
IN
Country
United States
Zip Code
47401
Zhong, Haixing; Tong, Li; Gu, Ning et al. (2017) Endocannabinoid signaling in hypothalamic circuits regulates arousal from general anesthesia in mice. J Clin Invest 127:2295-2309
Slivicki, Richard A; Xu, Zhili; Kulkarni, Pushkar M et al. (2017) Positive Allosteric Modulation of Cannabinoid Receptor Type 1 Suppresses Pathological Pain Without Producing Tolerance or Dependence. Biol Psychiatry :
Ruehle, Sabine; Wager-Miller, James; Straiker, Alex et al. (2017) Discovery and characterization of two novel CB1 receptor splice variants with modified N-termini in mouse. J Neurochem 142:521-533
Mitjavila, Jose; Yin, Danielle; Kulkarni, Pushkar M et al. (2017) Enantiomer-specific positive allosteric modulation of CB1 signaling in autaptic hippocampal neurons. Pharmacol Res :
Khurana, Leepakshi; Mackie, Ken; Piomelli, Daniele et al. (2017) Modulation of CB1 cannabinoid receptor by allosteric ligands: Pharmacology and therapeutic opportunities. Neuropharmacology 124:3-12
Xu, Changqing; Hermes, Douglas J; Nwanguma, Blessing et al. (2017) Endocannabinoids exert CB1 receptor-mediated neuroprotective effects in models of neuronal damage induced by HIV-1 Tat protein. Mol Cell Neurosci 83:92-102
Cinar, Resat; Gochuico, Bernadette R; Iyer, Malliga R et al. (2017) Cannabinoid CB1 receptor overactivity contributes to the pathogenesis of idiopathic pulmonary fibrosis. JCI Insight 2:
Dhopeshwarkar, Amey; Murataeva, Natalia; Makriyannis, Alex et al. (2017) Two Janus Cannabinoids That Are Both CB2 Agonists and CB1 Antagonists. J Pharmacol Exp Ther 360:300-311
Li, Ai-Ling; Carey, Lawrence M; Mackie, Ken et al. (2017) Cannabinoid CB2 Agonist GW405833 Suppresses Inflammatory and Neuropathic Pain through a CB1 Mechanism that is Independent of CB2 Receptors in Mice. J Pharmacol Exp Ther 362:296-305
Marcus, David J; Henderson-Redmond, Angela N; Gonek, Maciej et al. (2017) Mice expressing a ""hyper-sensitive"" form of the CB1 cannabinoid receptor (CB1) show modestly enhanced alcohol preference and consumption. PLoS One 12:e0174826

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