Enhancement of the behavioral effects of endogenous and exogenous cannabinoid agonists by phenylmethyl sulfonyl fluoride

Vann, Robert E.; Walentiny, D. Matthew; Burston, James J.; Tobey, K.M.; Gamage, Thomas F.; Wiley, Jenny L.

doi:10.1016/j.neuropharm.2011.10.011

Cited by 10 publications

(11 citation statements)

References 51 publications

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“…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). Interestingly, PF3845 did not shift the THC dose-effect curve, as did PMSF in a previous study (Vann et al, 2012), suggesting that PMSF may have produced the observed shift through greater magnitude of inhibition of endogenous anandamide (see PMSF in vitro data; Vann et al, 2012) or through inhibition of a non-FAAH pathway.…”

Section: 0 Discussionmentioning

confidence: 54%

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: 54%

Endocannabinoid contribution to Δ9-tetrahydrocannabinol discrimination in rodents

Wiley

Walentiny

Wright

et al. 2014

European Journal of Pharmacology

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“…The present study is one in a series of studies conducted in our lab that were designed, in part, to examine the role of endocannabinoids in THC's discriminative stimulus effects (Ignatowska-Jankowska et al 2014; Vann et al 2012; Walentiny et al 2011; Wiley et al 2014). In this study, a combination of genetically altered mice (FAAH knockout and widltype) and pharmacological probes (THC, anandamide, O-1812, JZL184, JZL195) were used to manipulate brain levels of anandamide and/or 2-AG.…”

Section: Discussionmentioning

confidence: 99%

Phenotypic assessment of THC discriminative stimulus properties in fatty acid amide hydrolase knockout and wildtype mice

2015

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A number of studies have examined the ability of the endogenous cannabinoid anandamide to elicit Δ9 -tetrahydrocannabinol (THC)-like subjective effects, as modeled through the THC discrimination paradigm. In the present study, we compared transgenic mice lacking fatty acid amide hydrolase (FAAH), the enzyme primarily responsible for anandamide catabolism, to wildtype counterparts in a THC discrimination procedure. THC (5.6 mg/kg) served as a discriminative stimulus in both genotypes, with similar THC dose-response curves between groups. Anandamide fully substituted for THC in FAAH knockout, but not wildtype, mice. Conversely, the metabolically stable anandamide analog O-1812 fully substituted in both groups, but was more potent in knockouts. The CB1 receptor antagonist rimonabant dose-dependently attenuated THC generalization in both groups and anandamide substitution in FAAH knockouts. Pharmacological inhibition of monoacylglycerol lipase (MAGL), the primary catabolic enzyme for the endocannabinoid 2-arachidonoylglycerol (2-AG), with JZL184 resulted in full substitution for THC in FAAH knockout mice and nearly full substitution in wildtypes. Quantification of brain endocannabinoid levels revealed expected elevations in anandamide in FAAH knockout mice compared to wildtypes and equipotent dose-dependent elevations in 2-AG following JZL184 administration. Dual inhibition of FAAH and MAGL with JZL195 resulted in roughly equipotent increases in THC-appropriate responding in both groups. While the notable similarity in THC's discriminative stimulus effects across genotype suggests that the increased baseline brain anandamide levels (as seen in FAAH knockout mice) do not alter THC's subjective effects, FAAH knockout mice are more sensitive to the THC-like effects of pharmacologically induced increases in anandamide and MAGL inhibition (e.g., JZL184).

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“…Investigations of the discriminative-stimulus effects of endogenous cannabinoids have produced somewhat conflicting results. In several drug-discrimination studies, anandamide did not produce THC-like effects in monkeys or rodents, or did so only at high doses that also depressed rates of responding (Burkey & Nation, 1997; Wiley et al, 1997, 1998; Jarbe et al, 2001; Wiley et al, 2004; Solinas et al, 2007; Vann et al, 2009, 2012), while other studies with rhesus monkeys have shown full THC-like effects of anandamide even at doses that did not affect rates of responding (McMahon, 2009; Stewart & McMahon, 2011). Although the reason for these discrepancies is unclear, it is likely that the weakness of anandamide’s THC-like discriminative-stimulus effects in some studies is due to anandamide’s rapid metabolic inactivation.…”

Section: Fatty Acid Amide Hydrolase Inhibition and Addictionmentioning

confidence: 93%

Inhibition of FAAH and activation of PPAR: New approaches to the treatment of cognitive dysfunction and drug addiction

Panlilio

Justinová

Goldberg

2013

Pharmacology & Therapeutics

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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.

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Enhancement of the behavioral effects of endogenous and exogenous cannabinoid agonists by phenylmethyl sulfonyl fluoride

Cited by 10 publications

References 51 publications

Endocannabinoid contribution to Δ9-tetrahydrocannabinol discrimination in rodents

Endocannabinoid contribution to Δ9-tetrahydrocannabinol discrimination in rodents

Phenotypic assessment of THC discriminative stimulus properties in fatty acid amide hydrolase knockout and wildtype mice

Inhibition of FAAH and activation of PPAR: New approaches to the treatment of cognitive dysfunction and drug addiction

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