The endocannabinoid (eCB) system is one of several lipid signaling systems in the brain and in the body. Verified components of this system include two G-protein coupled receptors, their signaling pathways, two predominant endogenous ligands [anandamide (AEA) and 2-arachidonyl glycerol (2-AG)], and their synthetic and metabolic pathways. The system plays an important modulatory role in many crucial CNS processes (e.g., brain reward, appetite regulation, cognition). Consequently, it is not surprising that this system has been implicated in the pathophysiology of a variety of health problems related to these processes, including substance abuse, eating disorders, other types of addictive behavior, and psychiatric disorders. Although research in cells or tissues suggest that there are differences between AEA and 2-AG, examination of potential behavioral consequences of these differences is sparse. Yet, the health problems, for which dysregulation of eCBs in the CNS is most strongly implicated, are problems in which behavior is central. Hence, one of the first steps towards delineation of physiological role(s) that AEA and/or 2-AG may play in health problems such as substance abuse is to distinguish similarities and differences in effects of these two eCBs in pharmacologically selective and validated behavioral procedures relevant to cannabinoid abuse. To this end, two mouse models, drug discrimination and intracranial self-stimulation (ICSS), will be used (Aims 1 and 2). Drug discrimination is an animal model of the subjective effects of psychoactive drugs in humans whereas ICSS represents a method used to evaluate the effects of drugs and behavioral or genetic manipulations on brain reward processes. Each of these factors is known to play a strong role in substance abuse. In addition, brain reward processes undoubtedly are involved in other forms of addictive behavior such as binge eating. The primary guiding idea underlying the proposed studies is that finer distinctions among functions of individual eCBs will be facilitated by knowing the extent to which their behavioral endpoints differ. Further, selected pharmacodynamic mechanisms that may be responsible for differences in the behavioral profiles of these eCBs will be examined (Aim 3). Namely, the relative efficacies and potencies of AEA and 2-AG at a level signal transduction that is a proximal to the ligand-receptor interaction (G-protein activation) will be determined, as the nature of this interaction is associated with alterations in behavioral responses. Results of the proposed studies will enhance understanding of how the eCB system (and especially each of the two major eCBs, AEA and 2-AG) is involved in physiological and pathophysiological processes related to substance abuse. This knowledge, combined with the current rapid development of pharmacological tools to manipulate this system (e.g., inhibitors of eCB synthesis and metabolism), also has the potential to lead to more effective therapeutic agents for health problems related to dysregulation of the eCB system.
Anandamide (AEA) and 2-arachidonyl glycerol (2-AG), the two primary endocannabinoids, play an important modulatory role in many crucial CNS processes such as brain reward, appetite regulation, and cognition. Previous research suggests that dysregulation of the endocannabinoid system is one of the mechanisms involved in substance abuse. Distinguishing the individual roles of AEA and 2-AG in processes related to substance abuse (i.e., subjective effects and brain reward), as is proposed in this project, has the potential to increase understanding of the physiological role(s) of the endocannabinoid system and to serve as a basis for rational choice of pharmacological tools to manipulate this system for therapeutic purposes.
|Owens, Robert A; Ignatowska-Jankowska, Bogna; Mustafa, Mohammed et al. (2016) Discriminative Stimulus Properties of the Endocannabinoid Catabolic Enzyme Inhibitor SA-57 in Mice. J Pharmacol Exp Ther 358:306-14|
|Ignatowska-Jankowska, Bogna; Wilkerson, Jenny L; Mustafa, Mohammed et al. (2015) Selective monoacylglycerol lipase inhibitors: antinociceptive versus cannabimimetic effects in mice. J Pharmacol Exp Ther 353:424-32|
|Walentiny, D Matthew; Vann, Robert E; Wiley, Jenny L (2015) Phenotypic assessment of THC discriminative stimulus properties in fatty acid amide hydrolase knockout and wildtype mice. Neuropharmacology 93:237-42|
|Wiebelhaus, Jason M; Grim, Travis W; Owens, Robert A et al. (2015) ?9-tetrahydrocannabinol and endocannabinoid degradative enzyme inhibitors attenuate intracranial self-stimulation in mice. J Pharmacol Exp Ther 352:195-207|
|Hruba, Lenka; Seillier, Alexandre; Zaki, Armia et al. (2015) Simultaneous inhibition of fatty acid amide hydrolase and monoacylglycerol lipase shares discriminative stimulus effects with ?9-tetrahydrocannabinol in mice. J Pharmacol Exp Ther 353:261-8|
|Ignatowska-Jankowska, Bogna M; Baillie, Gemma L; Kinsey, Steven et al. (2015) A Cannabinoid CB1 Receptor-Positive Allosteric Modulator Reduces Neuropathic Pain in the Mouse with No Psychoactive Effects. Neuropsychopharmacology 40:2948-59|
|Gamage, Thomas F; Ignatowska-Jankowska, Bogna M; Wiley, Jenny L et al. (2014) In-vivo pharmacological evaluation of the CB1-receptor allosteric modulator Org-27569. Behav Pharmacol 25:182-5|
|Ignatowska-Jankowska, B M; Ghosh, S; Crowe, M S et al. (2014) In vivo characterization of the highly selective monoacylglycerol lipase inhibitor KML29: antinociceptive activity without cannabimimetic side effects. Br J Pharmacol 171:1392-407|
|Wiley, Jenny L; Walentiny, D Matthew; Wright Jr, M Jerry et al. (2014) Endocannabinoid contribution to ?9-tetrahydrocannabinol discrimination in rodents. Eur J Pharmacol 737:97-105|
|Vann, R E; Walentiny, D M; Burston, J J et al. (2012) Enhancement of the behavioral effects of endogenous and exogenous cannabinoid agonists by phenylmethyl sulfonyl fluoride. Neuropharmacology 62:1019-27|
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