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

Walentiny, D. Matthew; Gamage, Thomas F.; Warner, Jonathan A.; Nguyen, Thanh Kim; Grainger, Darren B.; Wiley, Jenny L.; Vann, Robert E.

doi:10.1016/j.ejphar.2011.01.056

Cited by 15 publications

(15 citation statements)

References 52 publications

(57 reference statements)

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“…The results with PF3845 are consistent with those of previous studies, in which inhibition of anandamide metabolism with URB597 (Solinas et al, 2007) or with phenylmethyl sulfonyl fluoride (PMSF) (Vann et al, 2009) also enhanced anandamide substitution. Cross-substitution of THC for anandamide has also been demonstrated in FAAH(−/−) mice trained to discriminate anandamide from vehicle (Walentiny et al, 2011). Together, these results suggest an overlap in the discriminative stimulus effects of anandamide and THC when the rapid metabolism of anandamide is inhibited, although the present URB597 results are at odds with this interpretation (however, see next paragraph).…”

Section: 0 Discussionmentioning

confidence: 91%

“…Anandamide typically does not substitute for THC unless its rapid metabolism by FAAH is inhibited through pharmacological or genetic means (Solinas et al, 2007; Vann et al, 2009; Walentiny et al, 2011). Notably, however, flooding of the system by exogenous administration of anandamide is generally necessary for this substitution to occur; i.e., FAAH inhibitors increase anandamide concentration in the brain, but when administered alone, do not substitute for THC.…”

Section: 0 Discussionmentioning

confidence: 99%

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Endocannabinoid contribution to Δ9-tetrahydrocannabinol discrimination in rodents

Wiley

Walentiny

Wright

et al. 2014

European Journal of Pharmacology

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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 3 mg/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 (10 mg/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.

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Section: 0 Discussionmentioning

confidence: 91%

Section: 0 Discussionmentioning

confidence: 99%

Endocannabinoid contribution to Δ9-tetrahydrocannabinol discrimination in rodents

Wiley

Walentiny

Wright

et al. 2014

European Journal of Pharmacology

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“…Notably, FAAH inhibitors do not substitute for the THC discriminative stimulus (Gobbi et al, 2005; Owens et al, 2016; Solinas et al, 2007; Wiley et al, 2014), but increases substitution of exogenously administered AEA (Solinas et al, 2007; Stewart and McMahon, 2011; Vann et al, 2012; Wiley et al, 2014). Moreover, FAAH (−/−) mice learn to discriminate AEA from vehicle, an effect that was blocked by the CB 1 receptor antagonist rimonabant (Walentiny et al, 2011). Whereas FAAH inhibitors lack intrinsic cannabimimetic subjective effects, MAGL inhibitors partially substitute for THC (Long et al, 2009a,b; Wiley et al, 2014; Walentiny et al, 2011), and fully substitute for the CP55,940 discriminative stimulus (Ignatowska-Jankowska et al, 2015).…”

Section: Introductionmentioning

confidence: 99%

“…Moreover, FAAH (−/−) mice learn to discriminate AEA from vehicle, an effect that was blocked by the CB 1 receptor antagonist rimonabant (Walentiny et al, 2011). Whereas FAAH inhibitors lack intrinsic cannabimimetic subjective effects, MAGL inhibitors partially substitute for THC (Long et al, 2009a,b; Wiley et al, 2014; Walentiny et al, 2011), and fully substitute for the CP55,940 discriminative stimulus (Ignatowska-Jankowska et al, 2015). …”

Section: Introductionmentioning

confidence: 99%

Inhibition of the endocannabinoid-regulating enzyme monoacylglycerol lipase elicits a CB1 receptor-mediated discriminative stimulus in mice

et al. 2017

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Substantial challenges exist for investigating the cannabinoid receptor type 1 (CB1)-mediated discriminative stimulus effects of the endocannabinoids, 2-arachidonoylglycerol (2-AG) and N-arach-idonoylethanolamine (anandamide; AEA), compared with exogenous CB1 receptor agonists, such as Δ9-tetrahydrocannabinol (THC) and the synthetic cannabinoid CP55,940. Specifically, each endocannabinoid is rapidly degraded by the respective hydrolytic enzymes, monoacylglycerol lipase (MAGL) and fatty acid amide hydrolase (FAAH). Whereas MAGL inhibitors partially substitute for THC and fully substitute for CP55,940, FAAH inhibitors do not substitute for either drug. Interestingly, combined FAAH-MAGL inhibition results in full THC substitution, and the dual FAAH-MAGL inhibitor SA-57 serves as its own discriminative training stimulus. Because MAGL inhibitors fully substitute for SA-57, we tested whether the selective MAGL inhibitor MJN110 would serve as a training stimulus. Twelve of 13 C57BL/6J mice learned to discriminate MJN110 from vehicle, and the CB1 receptor antagonist rimonabant dose-dependently blocked its discriminative stimulus. CP55,940, SA-57, and another MAGL inhibitor JZL184, fully substituted for MJN110. In contrast, the FAAH inhibitor PF-3845 failed to substitute for the MJN110 discriminative stimulus, but produced a 1.6 (1.1–2.2; 95% confidence interval) leftward shift in the MJN110 dose-response curve. Inhibitors of other relevant enzymes (i.e., ABHD6, COX-2) and nicotine did not engender substitution. Diazepam partially substituted for MJN110, but rimonabant failed to block this partial effect. These findings suggest that MAGL normally throttles 2-AG stimulation of CB1 receptors to a magnitude insufficient to produce cannabimimetic subjective effects. Accordingly, inhibitors of this enzyme may release this endogenous brake producing effects akin to those produced by exogenously administered cannabinoids.

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“…AEA substitution in THC discrimination has also been reported in FAAH (−/−) mice (Walentiny et al, 2015). Further, FAAH (−/−) mice have been trained to discriminate AEA from vehicle, with cross-substitution of THC for AEA (Walentiny et al, 2011). …”

Section: Introductionmentioning

confidence: 99%

Just add water: cannabinoid discrimination in a water T-maze with FAAH(−/−) and FAAH(+/+) mice

Wiley

Lefever

Pulley

et al. 2016

Behavioural Pharmacology

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Incomplete overlap in the discriminative stimulus effects of Δ9-tetrahydrocannabinol (THC) and the endocannabinoids, anandamide (AEA) and 2-arachidonoylglycerol (2-AG), has been reported in food-reinforced tasks. The objective of this study was to examine cannabinoid discriminative stimulus effects in a non-appetitive procedure. Adult male mice lacking the gene for AEA’s major metabolic enzyme, fatty acid amide hydrolase (FAAH), and FAAH(+/+) mice were trained to discriminate THC or AEA in a water T-maze, in which the response was swimming to an escape platform on the injection-appropriate side. JZL184, a monoacylglycerol lipase (MAGL) inhibitor, was also tested. FAAH(−/−) mice exhibited speedier acquisition than FAAH(+/+) mice. THC and AEA fully substituted, with only minor cross-procedure potency variations. Incomplete substitution of JZL184 was observed in THC-trained FAAH(−/−) mice in the water maze task, as contrasted with full substitution in a food-reinforced nose-poke procedure. Stress-induced changes in AEA and/or 2-AG concentrations in the brain may have mediated this attenuation. JZL184 also partially substituted in AEA-trained FAAH(−/−) mice in the water maze, suggesting incomplete overlap in the stimulus effects of AEA and JZL184. Through use of a novel water maze procedure, the present study supports the work of previous behavioral pharmacologists in demonstrating robustness of the discrimination paradigm.

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

Cited by 15 publications

References 52 publications

Endocannabinoid contribution to Δ9-tetrahydrocannabinol discrimination in rodents

Endocannabinoid contribution to Δ9-tetrahydrocannabinol discrimination in rodents

Inhibition of the endocannabinoid-regulating enzyme monoacylglycerol lipase elicits a CB1 receptor-mediated discriminative stimulus in mice

Just add water: cannabinoid discrimination in a water T-maze with FAAH(−/−) and FAAH(+/+) mice

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