The overall purpose of the proposed studies is to compare the structure- activity relationships of the subjective effects of delta-9- tetrahydrocannabinol (delta-9-THC) and other cannabimimetics with an analog (R-methanandamide) of the endogenous cannabinoid receptor ligand anandamide. The SAR between chemical structure and drug action reveals the structural requirements for a given drug effect or drug action. Though some studies suggest that delta-9-THC and anandamide as well as R-methanandamide share many similar properties, a one-on-one relationship has not been demonstrated. Studies from our own and other laboratories have shown the THC-like properties of synthetic cannabinoids and cannabimimetics are highly dependent on particular structural configurations. The proposed studies investigate potential stereoselectivity of known cannabimimetic compounds with regard to R- methanandamide. These studies also focus on identifying useful pharmacotherapies for cannabis abuse by effectively blocking the psychoactive, cannabimimetic properties. The present project will utilize drug discrimination procedures with rats as an animal model for assessing the psychoactive properties of delta-9-THC, R-methanandamide, and related compounds. Drug discrimination is the most commonly used paradigm for studying the subjective, intoxicating effects of drugs in preclinical psychopharmacology. A special feature of this proposal is the use of different training doses of THC to create different efficacy demands. Additionally, food maintained responding and open-field activity studies will also be conducted. By providing important information on the SAR of endogenous anandamide and exogenous delta-9- THC, as well as potential cannabimimetic antagonists, these studies will not only add to our understanding of the behavioral neurobiology of cannabis abuse and dependence, but may also lead to the development of effective pharmacological treatments.

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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Schnur, Paul
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Temple University
Schools of Arts and Sciences
United States
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Järbe, Torbjörn U C; Raghav, Jimit Girish (2017) Tripping with Synthetic Cannabinoids (""Spice""): Anecdotal and Experimental Observations in Animals and Man. Curr Top Behav Neurosci 32:263-281
Järbe, Torbjörn U C; LeMay, Brian J; Thakur, Ganesh A et al. (2016) A high efficacy cannabinergic ligand (AM4054) used as a discriminative stimulus: Generalization to other adamantyl analogs and ?(9)-THC in rats. Pharmacol Biochem Behav 148:46-52
Järbe, Torbjörn U C; Gifford, Roger S; Zvonok, Alexander et al. (2016) [INCREMENT]9-Tetrahydrocannabinol discriminative stimulus effects of AM2201 and related aminoalkylindole analogs in rats. Behav Pharmacol 27:211-4
Nikas, Spyros P; Sharma, Rishi; Paronis, Carol A et al. (2015) Probing the carboxyester side chain in controlled deactivation (-)-?(8)-tetrahydrocannabinols. J Med Chem 58:665-81
Tai, Sherrica; Nikas, Spyros P; Shukla, Vidyanand G et al. (2015) Cannabinoid withdrawal in mice: inverse agonist vs neutral antagonist. Psychopharmacology (Berl) 232:2751-61
Järbe, Torbjörn U C; Gifford, Roger S (2014) ""Herbal incense"": designer drug blends as cannabimimetics and their assessment by drug discrimination and other in vivo bioassays. Life Sci 97:64-71
Sharma, Rishi; Nikas, Spyros P; Guo, Jason Jianxin et al. (2014) C-ring cannabinoid lactones: a novel cannabinergic chemotype. ACS Med Chem Lett 5:400-4
Järbe, Torbjörn U C; LeMay, Brian J; Halikhedkar, Aneetha et al. (2014) Differentiation between low- and high-efficacy CB1 receptor agonists using a drug discrimination protocol for rats. Psychopharmacology (Berl) 231:489-500
Sharma, Rishi; Nikas, Spyros P; Paronis, Carol A et al. (2013) Controlled-deactivation cannabinergic ligands. J Med Chem 56:10142-57
Järbe, Torbjörn U C; Tai, Sherrica; LeMay, Brian J et al. (2012) AM2389, a high-affinity, in vivo potent CB1-receptor-selective cannabinergic ligand as evidenced by drug discrimination in rats and hypothermia testing in mice. Psychopharmacology (Berl) 220:417-26

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