Article

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: 2.59). 02/2011; 656(1-3):63-7. DOI: 10.1016/j.ejphar.2011.01.056
Source: PubMed

ABSTRACT 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.

0 Bookmarks
 · 
115 Views
  • [Show abstract] [Hide abstract]
    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.
    Pharmacology [?] Therapeutics 01/2013; · 7.79 Impact Factor
  • Source
    [Show abstract] [Hide abstract]
    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'.
    Neuropharmacology 10/2011; 62(2):1019-27. · 4.11 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: The mechanism through which marijuana produces its psychoactive effects is Δ9- tetrahydrocannabinol (THC)-induced activation of cannabinoid CB1 receptors. These receptors are normally activated by endogenous lipids, including anandamide and 2-arachidonoyl glycerol (2-AG). A logical "first step" in determination of the role of these endocannabinoids in THC's psychoactive effects is to investigate the degree to which pharmacologically induced increases in anandamide and/or 2-AG concentrations through exogenous administration and/or systemic administration of inhibitors of their metabolism, fatty acid amide hydrolase (FAAH) or monoacylglycerol lipase (MAGL), respectively, share THC's discriminative stimulus effects. To this end, adult male mice and rats were trained to discriminate THC (5.6 and 3mg/kg, respectively). In Experiment 1, exogenous administration of anandamide or 2-AG did not substitute for THC in mice nor was substitution enhanced by co-administration of the FAAH or MAGL inhibitors, URB597 and N-arachidonyl maleimide (NAM), respectively. Significant decreases in responding may have prevented assessment of adequate endocannabinoid doses. In mice trained at higher baseline response rates (Experiment 2), the FAAH inhibitor PF3845 (10mg/kg) enhanced anandamide substitution for THC without producing effects of its own. The MAGL inhibitor JZL184 increased brain levels of 2-AG in vitro and in vivo, increased THC-like responding without co-administration of 2-AG. In rats, neither URB597 nor JZL184 engendered significant THC-appropriate responding, but co-administration of these two enzyme inhibitors approached full substitution. The present results highlight the complex interplay between anandamide and 2-AG and suggest that endogenous increases of both endocannabinoids are most effective in elicitation of THC-like discriminative stimulus effects
    European Journal of Pharmacology 05/2014; · 2.59 Impact Factor

Full-text (2 Sources)

View
17 Downloads
Available from
May 31, 2014