The endogenous cannabinoid anandamide shares discriminative stimulus effects with ∆9-tetrahydrocannabinol in fatty acid amide hydrolase knockout mice

Department of Pharmacology and Toxicology, Virginia Commonwealth University, 410 North 12th Street, PO BOX 980613, Richmond, VA 23298-0613, United States.
European journal of pharmacology (Impact Factor: 2.53). 02/2011; 656(1-3):63-7. DOI: 10.1016/j.ejphar.2011.01.056
Source: PubMed


The endogenous cannabinoid system has been noted for its therapeutic potential, as well as the psychoactivity of cannabinoids such as Δ9-tetrahydrocannabinol (THC). However, less is known about the psychoactivity of anandamide (AEA), an endocannabinoid ligand. Thus, the goals of this study were to establish AEA as a discriminative stimulus in transgenic mice lacking fatty acid amide hydrolase (i.e., FAAH -/- mice unable to rapidly metabolize AEA), evaluate whether THC or oleamide, a fatty acid amide, produced AEA-like responding, and assess for CB(1) mediation of AEA's discriminative stimulus. Mice readily discriminated between 6mg/kg AEA and vehicle in a two-lever drug discrimination task. AEA dose-dependently generalized to itself. THC elicited full AEA-like responding, whereas oleamide failed to substitute. The CB(1) antagonist rimonabant attenuated AEA- and THC-induced AEA-appropriate responding, demonstrating CB(1) mediation of AEA's discriminative stimulus. These findings suggest that, in the absence of FAAH, AEA produces intoxication comparable to THC, and consequently to marijuana.

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Available from: Robert Vann, Feb 10, 2014
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    • "FAAH knockout mice can be trained to discriminate THC about as well as their wild-type littermates can (Long et al., 2009). FAAH knockouts can also be trained to discriminate anandamide from vehicle (Walentiny et al., 2011), and in these animals both THC and various doses of anandamide elicit full anandamide-like responding, which is attenuated by the CB 1 antagonist/inverse agonist rimonabant. Thus, in the absence of FAAH, anandamide produces subjective effects comparable to those of THC. "
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    ABSTRACT: Enhancing the effects of endogenously-released cannabinoid ligands in the brain might provide therapeutic effects more safely and effectively than administering drugs that act directly at the cannabinoid receptor. Inhibitors of fatty acid amide hydrolase (FAAH) prevent the breakdown of endogenous ligands for cannabinoid receptors and peroxisome proliferator-activated receptors (PPAR), prolonging and enhancing the effects of these ligands when they are naturally released. This review considers recent research on the effects of FAAH inhibitors and PPAR activators in animal models of addiction and cognition (specifically learning and memory). These studies show that FAAH inhibitors can produce potentially therapeutic effects, some through cannabinoid receptors and some through PPAR. These effects include enhancing certain forms of learning, counteracting the rewarding effects of nicotine and alcohol, relieving symptoms of withdrawal from cannabis and other drugs, and protecting against relapse-like reinstatement of drug self-administration. Since FAAH inhibition might have a wide range of therapeutic actions but might also share some of the adverse effects of cannabis, it is noteworthy that at least one FAAH-inhibiting drug (URB597) has been found to have potentially beneficial effects but no indication of liability for abuse or dependence. Although these areas of research are new, the preliminary evidence indicates that they might lead to improved therapeutic interventions and a better understanding of the brain mechanisms underlying addiction and memory.
    Full-text · Article · Jan 2013 · Pharmacology [?] Therapeutics
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    • "Through pharmacological inhibition of FAAH, AEA has been found to produce THC-like discriminative stimulus in both rats (Solinas et al., 2007) and mice (Vann et al., 2009). Conversely, THC fully substitutes in FAAH knockout mice trained to discriminate anandamide versus vehicle (Walentiny et al., 2011). These studies have demonstrated that anandamide shares discriminative stimulus properties with THC. "
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    ABSTRACT: Marijuana's effects in humans are most often reported as intoxicating or therapeutic; yet, some humans report dysphoria or other negative affect. To evaluate whether differences in endocannabinoid levels might account for this variability, the present study examined whether sensitivity to cannabinoids changed when anandamide (AEA) metabolism was inhibited through administration of phenylmethyl sulfonyl fluoride (PMSF) a non-specific irreversible amidase inhibitor. Male Long Evans rats were trained to discriminate 3 mg/kg Δ(9)-tetrahydrocannabinol (THC) versus vehicle in 2-lever drug discrimination procedure. ED(50)s for THC and CP 55,940 were lower when administered with PMSF than alone. PMSF administration also potentiated characteristic cannabimimetic effects of THC in ICR mice. Potentiation of AEA's in vivo effects by PMSF were also observed, primarily as a consequence of PMSF inhibition of the enzyme fatty acid amide hydrolase. Enhancement of the effects of THC and CP 55,940 through this mechanism is unlikely, as these cannabinoids are predominantly metabolized through the P450 system. Mass spectrometry revealed that, in the presence of THC, endogenous AEA levels in the brain decreased and that this decrease was prevented by PMSF, suggesting that increased AEA levels may have acted additively with exogenously administered cannabinoids to increase cannabimimetic effects. These findings may account for the varying affect in response to marijuana in humans or cannabinoids in animals while also suggesting that metabolic inhibitors of AEA may potentiate marijuana's intoxicating effects in humans. This article is part of a Special Issue entitled 'Post-Traumatic Stress Disorder'.
    Full-text · Article · Oct 2011 · Neuropharmacology
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    • "methanandamide-like) discriminative stimulus effects. In addition to supporting previous research in rats, these results are consistent with our recent report that THC generalizes to anandamide in FAAH −/− mice trained to discriminate anandamide from vehicle (Walentiny et al., 2011). Notably, anandamide also generalized to methanandamide even in the absence of metabolism inhibition, albeit it was slightly less efficacious than the training drug. "
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    ABSTRACT: Δ(9)-Tetrahydrocannabinol (THC) discrimination in rodents is a behavioral assay that has been used to probe differences among classes of cannabinoids in rats. The purpose of this study was to determine whether traditional and anandamide-like cannabinoids were distinguishable in cannabinoid discrimination procedures in mice. Male mice were trained to discriminate 30 mg/kg THC or 70 mg/kg methanandamide from vehicle in a two-lever milk-reinforced drug discrimination procedure. After acquisition, agonist tests with THC, methanandamide, CP 55940, and anandamide were conducted, as were antagonism tests with rimonabant. Substitution (agonism) and antagonism tests were also carried out in female mice trained to discriminate THC. THC and CP 55940 fully substituted in THC-trained mice of both sexes. Further, THC substitution was rimonabant reversible. In contrast, mice injected with methanandamide or anandamide failed to respond substantially on the THC lever, even up to doses that decreased overall responding. In methanandamide-trained mice, methanandamide fully generalized to the methanandamide training dose. Rimonabant did not reverse this generalization. Although THC, CP 55940, and anandamide also increased responding on the methanandamide lever, the magnitude of substitution was less than for methanandamide. These results suggest incomplete overlap in the underlying mechanisms mediating endocannabinoid pharmacology and marijuana intoxication. Further, they suggest that methanandamide discrimination may involve a non-CB(1) receptor mechanism that is particularly prominent at higher doses.
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