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Journal of Pharmacology And Experimental Therapeutics Fast Forward
First published on January 8, 2007; DOI: 10.1124/jpet.106.114124

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*TETRAHYDROCANNABINOL


Received for publication September 20, 2006.
Revised January 4, 2007.
Accepted for publication January 5, 2007.

The endogenous cannabinoid anandamide produces THC-like discriminative and neurochemical effects that are enhanced by inhibition of fatty acid amide hydrolase (FAAH) but not by inhibition of anandamide transport

Marcello Solinas 1, Gianluigi Tanda 2, Zuzana Justinova 3, Carrie E Wertheim 4, Sevil Yasar 5, Daniele Piomelli 6, Subramanian K Vadivel 7, Alexandros Makriyannis 7, Steven R. Goldberg 8*

1 CNRS6187 2 National Institute on Drug Abuse, NIH, DHHS 3 University of Maryland School of Medicine 4 ational Institute on Drug Abuse, NIH, DHHS 5 Johns Hopkins University 6 Univ. of California - Irvine 7 Center for Drug Discovery, Northeastern University, Boston 8 NIDA/IRP, NIH, DHHS

* Address correspondence to: E-mail: sgoldber{at}intra.nida.nih.gov

Abstract

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 intravenously (i.v.) or intraperitoneally, would produce discriminative effects like those of delta-9-tetrahydrocannabinol (THC) in rats when its metabolic inactivation was inhibited. We also used an in-vivo microdialysis procedure to investigate effects of anandamide, given i.v. or intraperitoneally, 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. URB-597, an inhibitor of fatty acid amide hydrolase (FAAH), the main enzyme responsible for anandamide's metabolic inactivation, 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 anandamide's ability to increase dopamine levels in the accumbens shell. The THC-like discriminative-stimulus effects of methanandamide and anandamide after URB-597 were blocked by the CB1 receptor antagonist rimonabant, but not the vanilloid VR1 receptor antagonist capsazepine. Surprisingly, the anandamide transport inhibitors AM-404 and UCM-707 did not potentiate anandamide's THC-like discriminative effects 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 vs. transport/FAAH inactivation of anandamide.


Key words: THC, anandamide, dopamine, drug-discrimination, nucleus accumbens, rat


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