This proposal is a request for a RSDA which would facilitate and extend ongoing research concerning cannabinoids and related compounds. The recent advances in our understanding of the neurochemical/physiological basis of cannabinoid action provide exciting background material for continuing efforts to further delineate the mechanism of action of cannabimimetic agents. The overall purpose of the proposed studied is to compare the structure-activity relationships of the subjective effects of delta9-tetrahydrocannabinol (delta9-THC) and the endogenous cannabinoid receptor ligand anandamide. The SAR between chemical structure and drug action reveals the structural requirements for the stereoselectivity or stereospecificity of a given drug effect or drug action. Though some studies suggest that delta9-THC and anandamide 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. In general, these studies suggest that cannabimimetic activity is stereoselective, i.e., whether the compound is a (+ )- or (-)-enantiomer, methyl group planarity with regard to the cyclohexane ring, and characteristics of the side chain. The pro posed studies investigate, potential stereoselectivity of known cannabimimetic compounds with regard to anandamide. These studies also focus on identifying useful pharmacotherapies for cannabis abuse by effectively blocking the psychoactive, cannabimimetic properties. Though a number of compounds have been identified that have cannabimimetic properties, compounds that effectively block or antagonize the THC cue have not yet been isolated. The present project will primarily utilize drug discrimination procedures with rats as an animal model for assessing the psychoactive properties of delta9-THC, anandamide, and related test compounds. Drug discrimination is the most commonly used paradigm for studying the subjective, intoxicating effects of drugs in preclinical psychopharmacology.
The Aims of this proposal will be addressed in a series of 4 main experiments, requiring 5 years for full completion. The overall purpose is to: l) determine if the SAR of delta9-THC and anadamide are similar with regard to subjective discriminative stimulus properties, and 2) explore the potential for antagonism of cannabimimetic effects. By providing important information on the SAR of endogenous anandamide and exogenous delta9-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. Approval of this proposal would create financial stability and ensure that the above goals can be met.

Agency
National Institute of Health (NIH)
Institute
National Institute on Drug Abuse (NIDA)
Type
Research Scientist Development Award - Research (K02)
Project #
5K02DA000253-04
Application #
2733471
Study Section
Special Emphasis Panel (SRCD (27))
Program Officer
Schnur, Paul
Project Start
1995-07-15
Project End
1998-11-10
Budget Start
1998-07-01
Budget End
1998-11-10
Support Year
4
Fiscal Year
1998
Total Cost
Indirect Cost
Name
Allegheny University of Health Sciences
Department
Psychiatry
Type
Schools of Medicine
DUNS #
City
Philadelphia
State
PA
Country
United States
Zip Code
19129
Järbe, Torbjörn U C; Deng, Hongfen; Vadivel, Subramanian K et al. (2011) Cannabinergic aminoalkylindoles, including AM678=JWH018 found in 'Spice', examined using drug (?(9)-tetrahydrocannabinol) discrimination for rats. Behav Pharmacol 22:498-507
Järbe, Torbjörn U C; Li, Chen; Vadivel, Subramanian K et al. (2010) Discriminative stimulus functions of methanandamide and delta(9)-THC in rats: tests with aminoalkylindoles (WIN55,212-2 and AM678) and ethanol. Psychopharmacology (Berl) 208:87-98
Järbe, Torbjörn U C; Li, Chen; Liu, Qian et al. (2009) Discriminative stimulus functions in rats of AM1346, a high-affinity CB1R selective anandamide analog. Psychopharmacology (Berl) 203:229-39
Jarbe, T U C; LeMay, B J; Olszewska, T et al. (2008) Intrinsic effects of AM4113, a putative neutral CB1 receptor selective antagonist, on open-field behaviors in rats. Pharmacol Biochem Behav 91:84-90
Jarbe, Torbjorn U C; Li, Chen; Vadivel, Subramanian K et al. (2008) Discriminative stimulus effects of the cannabinoid CB1 receptor antagonist rimonabant in rats. Psychopharmacology (Berl) 198:467-78
Jarbe, Torbjorn U C; DiPatrizio, Nicholas V; Li, Chen et al. (2007) Effects of AM1346, a high-affinity CB1 receptor selective anandamide analog, on open-field behavior in rats. Behav Pharmacol 18:673-80
Jarbe, Torbjorn U C; Liu, Quian; Makriyannis, Alexandros (2006) Antagonism of discriminative stimulus effects of delta(9)-THC and (R)-methanandamide in rats. Psychopharmacology (Berl) 184:36-45
Jarbe, T U C; DiPatrizio, N V (2005) Delta9-THC induced hyperphagia and tolerance assessment: interactions between the CB1 receptor agonist delta9-THC and the CB1 receptor antagonist SR-141716 (rimonabant) in rats. Behav Pharmacol 16:373-80
Jarbe, T U C; DiPatrizio, N V; Lu, D et al. (2004) (-)-Adamantyl-delta8-tetrahydrocannabinol (AM-411), a selective cannabinoid CB1 receptor agonist: effects on open-field behaviors and antagonism by SR-141716 in rats. Behav Pharmacol 15:517-21
Jarbe, T U; Lamb, R J; Lin, S et al. (2000) Delta9-THC training dose as a determinant for (R)-methanandamide generalization in rats: a systematic replication. Behav Pharmacol 11:81-6

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