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BEHAVIORAL PHARMACOLOGY

The Endogenous Cannabinoid Anandamide Produces -9-Tetrahydrocannabinol-Like Discriminative and Neurochemical Effects That Are Enhanced by Inhibition of Fatty Acid Amide Hydrolase but Not by Inhibition of Anandamide Transport

Laboratoire de Biologie et Physiologie Cellulaires, CNRS-6187, Université de Poitiers, Poitiers, France (M.S.); Preclinical Pharmacology Section, Behavioral Neuroscience Research Branch (M.S., Z.J., C.E.W., S.R.G.) and Psychobiology Section, Medications Discovery Research Branch (G.T.), Intramural Research Program, National Institute on Drug Abuse, National Institutes of Health, Department of Health and Human Services, Baltimore, Maryland; Maryland Psychiatric Research Center, University of Maryland School of Medicine, Baltimore, Maryland (Z.J.); Division of Geriatric Medicine and Gerontology, Johns Hopkins University School of Medicine, Baltimore, Maryland (S.Y.); Department of Pharmacology, University of California, Irvine, California (D.P.); and Center for Drug Discovery, Bouve College of Health Sciences, Northeastern University, Boston, Massachusetts (A.M., S.K.V.)

Anandamide is an endogenous ligand for brain cannabinoid CB₁ receptors, but its behavioral effects are difficult to measure due to rapid inactivation. Here we used a drug-discrimination procedure to test the hypothesis that anandamide, given i.v. or i.p., would produce discriminative effects like those of -9-tetrahydrocannabinol (THC) in rats when its metabolic inactivation was inhibited. We also used an in vivo microdialysis procedure to investigate the effects of anandamide, given i.v. or i.p., on dopamine levels in the nucleus accumbens shell in rats. When injected i.v., methanandamide (AM-356), a metabolically stable anandamide analog, produced clear dose-related THC-like discriminative effects, but anandamide produced THC-like discriminative effects only at a high 10-mg/kg dose that almost eliminated lever-press responding. Cyclohexyl carbamic acid 3'-carbamoyl-biphenyl-3-yl ester (URB-597), an inhibitor of fatty acid amide hydrolase (FAAH), the main enzyme responsible for metabolic inactivation of anandamide, produced no THC-like discriminative effects alone but dramatically potentiated discriminative effects of anandamide, with 3 mg/kg anandamide completely substituting for the THC training dose. URB-597 also potentiated the ability of anandamide to increase dopamine levels in the accumbens shell. The THC-like discriminative-stimulus effects of anandamide after URB-597 and methanandamide were blocked by the CB₁ receptor antagonist rimonabant, but not the vanilloid VR₁ receptor antagonist capsazepine. Surprisingly, the anandamide transport inhibitors N-(4-hydroxyphenyl)-eicosa-5,8,11,14-tetraenamide (AM-404) and N-(3-furylmethyl)eicosa-5,8,11,14-tetraenamide (UCM-707) did not potentiate THC-like discriminative effects of anandamide or its dopamine-elevating effects. Thus, anandamide has THC-like discriminative and neurochemical effects that are enhanced after treatment with a FAAH inhibitor but not after treatment with transport inhibitors, suggesting brain area specificity for FAAH versus transport/FAAH inactivation of anandamide.

Address correspondence to: Dr. Steven Robert Goldberg, Preclinical Pharmacology Section, Intramural Research Program, National Institute on Drug Abuse, NIH, DHHS, 5500 Nathan Shock Drive, Baltimore, MD 21224. E-mail: sgoldber{at}intra.nida.nih.gov

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