Cannabinoid receptors are molecular targets for marijuana, the most widespread illegal drug of abuse in Western societies. Cannabinoid receptors are densely expressed in areas of the central nervous system (CNS) that participate in the control of pain perception, appetite, memory, cognition and movement. Such functions are strongly affected by cannabinoid drugs, with consequences that include analgesia, appetite stimulation, euphoria and memory impairment. Although the pharmacology of cannabinoid drugs is now beginning to be understood, the endogenous signaling system by which cannabinoid receptors are physiologically engaged remains largely unexplored. An endogenous ligand for cannabinoid receptors, anandamide, has been described. Anandamide is released from neurons on depolarization, and it undergoes a rapid process of biological inactivation. The molecular mechanisms underlying such inactivation are, however, still only partially understood. On the basis of our preliminary findings, we propose to test the hypothesis that carrier-mediated transport into neural cells constitutes a prominent route of anandamide inactivation in the CNS. To test this hypothesis it will be necessary to show that neural cells accumulate anandamide by a mechanism that fulfills the criteria of a carrier-mediated transport (i.e., time- and temperature-dependence, high affinity, substrate selectivity, and inhibition by specific agents). Moreover, it will be necessary to demonstrate that anandamide transport participates in terminating anandamide responses at its sites of action in the CNS.
The first aim of the proposed research is to investigate the mechanisms responsible for anandamide transport. Preliminary experiments suggested that rat brain neurons and astrocytes in primary culture accumulate anandamide by a carrier-mediated transport system. The proposed studies will characterize the mechanism of anandamide transport in these cells.
The second aim of our proposed research is to determine what are the structural determinants for anandamide transport. Preliminary experiments have shown that anandamide transport is highly specific. We will explore the structure activity relationship of anandamide transport, by designing and synthesizing novel anandamide-like compounds and test them for their ability to act as transport substrates or inhibitors.
The third aim of our proposal is to define the properties, topographic distribution and functional roles of anandamide transport in CNS. Initial experiments have indicated that rat brain slices accumulate anandamide by a transport mechanism similar to the one we have identified in cultured cells. The proposed research will characterize this transport, determine its topographic distribution in CNS, and investigate its role in the elimination of endogenous anandamide released by physiologically relevant stimuli. These studies will set the stage for the molecular characterization of the anandamide transporter protein and for the development of potent and selective anandamide transport inhibitors. In conclusion, by demonstrating that transmembrane transport participates in anandamide inactivation, our studies will shed new light on the mechanisms of marijuana abuse and help develop novel strategies in the therapy of neurological, psychiatric and substance abuse disorders.

National Institute of Health (NIH)
National Institute on Drug Abuse (NIDA)
Research Project (R01)
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Human Development Research Subcommittee (NIDA)
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Hillery, Paul
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University of California Irvine
Schools of Medicine
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Schoch, H; Huerta, M Y; Ruiz, C M et al. (2018) Adolescent cannabinoid exposure effects on natural reward seeking and learning in rats. Psychopharmacology (Berl) 235:121-134
Wang, W; Cox, B M; Jia, Y et al. (2018) Treating a novel plasticity defect rescues episodic memory in Fragile X model mice. Mol Psychiatry 23:1798-1806
Castellani, Beatrice; Diamanti, Eleonora; Pizzirani, Daniela et al. (2017) Synthesis and characterization of the first inhibitor of N-acylphosphatidylethanolamine phospholipase D (NAPE-PLD). Chem Commun (Camb) 53:12814-12817
Wei, Don; Allsop, Stephen; Tye, Kay et al. (2017) Endocannabinoid Signaling in the Control of Social Behavior. Trends Neurosci 40:385-396
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
Rock, Erin M; Moreno-Sanz, Guillermo; Limebeer, Cheryl L et al. (2017) Suppression of acute and anticipatory nausea by peripherally restricted fatty acid amide hydrolase inhibitor in animal models: role of PPAR? and CB1 receptors. Br J Pharmacol 174:3837-3847
Angelini, Roberto; Argueta, Donovan A; Piomelli, Daniele et al. (2017) Identification of a Widespread Palmitoylethanolamide Contamination in Standard Laboratory Glassware. Cannabis Cannabinoid Res 2:123-132
Wei, Don; Lee, DaYeon; Li, Dandan et al. (2016) A role for the endocannabinoid 2-arachidonoyl-sn-glycerol for social and high-fat food reward in male mice. Psychopharmacology (Berl) 233:1911-9
Scarpelli, Rita; Sasso, Oscar; Piomelli, Daniele (2016) A Double Whammy: Targeting Both Fatty Acid Amide Hydrolase (FAAH) and Cyclooxygenase (COX) To Treat Pain and Inflammation. ChemMedChem 11:1242-51
Migliore Dr, Marco; Pontis Dr, Silvia; Fuentes de Arriba, Angel Luis et al. (2016) Second-Generation Non-Covalent NAAA Inhibitors are Protective in a Model of Multiple Sclerosis. Angew Chem Int Ed Engl 55:11193-11197

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