Cannabinoid CB₁ Discrimination: Effects of Endocannabinoids and Catabolic Enzyme Inhibitors

Abstract

An improved understanding of the endocannabinoid system has provided new avenues of drug discovery and development toward the management of pain and other behavioral maladies. Exogenous cannabinoid type 1 (CB) receptor agonists such as Δ-tetrahydrocannabinol are increasingly used for their medicinal actions; however, their utility is constrained by concern regarding abuse-related subjective effects. This has led to growing interest in the clinical benefit of indirectly enhancing the activity of the highly labile endocannabinoids -arachidonoylethanolamine [AEA (or anandamide)] and/or 2-arachidonoylglycerol (2-AG) via catabolic enzyme inhibition. The present studies were conducted to determine whether such actions can lead to CB agonist-like subjective effects, as reflected in CB-related discriminative stimulus effects in laboratory subjects. Squirrel monkeys ( = 8) that discriminated the CB full agonist AM4054 (0.01 mg/kg) from vehicle were used to study, first, the inhibitors of fatty acid amide hydrolase (FAAH) or monoacylglycerol lipase (MGL) alone or in combination [FAAH (URB597, AM4303); MGL (AM4301); FAAH/MGL (JZL195, AM4302)] and, second, the ability of the endocannabinoids AEA and 2-AG to produce CB agonist-like effects when administered alone or after enzyme inhibition. Results indicate that CB-related discriminative stimulus effects were produced by combined, but not selective, inhibition of FAAH and MGL, and that these effects were nonsurmountably antagonized by low doses of rimonabant. Additionally, FAAH or MGL inhibition revealed CB-like subjective effects produced by AEA but not by 2-AG. Taken together, the present data suggest that therapeutic effects of combined, but not selective, enhancement of AEA or 2-AG activity via enzyme inhibition may be accompanied by CB receptor-mediated subjective effects.

Cannabinoid Antagonist Drug Discrimination in Nonhuman Primates

“…In this regard, neither the nonselective FAAH/MGL inhibitor AM4302 nor the FAAH-selective inhibitor URB597 similarly substituted for AM2389 in precluding rimonabant-lever responding. Although previous work in squirrel monkeys indicates that doses of URB597 and AM4302 studied here are pharmacologically active and that URB597 alone does not produce CB1-like effects (Justinova et al, 2008;Leonard et al, 2017), it remains possible that rimonabant-lever responding might have been attenuated by higher doses of AM4302. For example, Leonard et al (2017) showed that AM4302, like other nonselective FAAH/MGL inhibitors, is fully capable of producing a CB 1 discriminative stimulus in agonist-trained subjects.…”

“…Although previous work in squirrel monkeys indicates that doses of URB597 and AM4302 studied here are pharmacologically active and that URB597 alone does not produce CB1-like effects (Justinova et al, 2008;Leonard et al, 2017), it remains possible that rimonabant-lever responding might have been attenuated by higher doses of AM4302. For example, Leonard et al (2017) showed that AM4302, like other nonselective FAAH/MGL inhibitors, is fully capable of producing a CB 1 discriminative stimulus in agonist-trained subjects. Based on the potency relationship in the two types of discrimination studies discussed above, considerably higher doses of AM4302 than those tested here may be necessary to reduce rimonabant-lever responding.…”

“…60 minute prior to the session and evaluated during one component consisting of 20 trials. The pretreatment time and session duration were based on findings from preliminary time course experiments and previously published work in squirrel monkeys (Kangas et al, 2013(Kangas et al, , 2016Leonard et al, 2017). The order of drug testing varied among subjects.…”

Antiemetic Effects of Cannabinoid Agonists in Nonhuman Primates

“…This is a curious gap considering the limitations of rodent subjects in emesis research and substantial in vivo cannabinoid research that has been conducted in nonhuman primates. In particular, squirrel monkeys, in which cannabinoids have been extensively studied (e.g., Branch et al, 1980;Tanda et al, 2000;Justinova et al, 2003Justinova et al, , 2013Solinas et al, 2007;Kangas and Bergman, 2012;Desai et al, 2013;Kangas et al, 2013Kangas et al, , 2016Leonard et al, 2017) and which have an emetic response, are highly suitable for evaluating the antiemetic effects of cannabinoids. The present studies therefore examined D 9 -THC, the primary psychoactive constituent in cannabis, and methanandamide [mAEA; (R)-(+)-arachidonyl-19-hydroxy-29-propylamide], a metabolically stable analog of the endocannabinoid anandamide, for their ability to block emesis and prodromal hypersalivation in the squirrel monkey.…”

A Neglected Link Between the Psychoactive Effects of Dietary Ingredients and Consciousness-Altering Drugs

“…When mixed with N-linoleoylethanolamide and N-oleoylethanolamide from cacao, which inhibit anandamide breakdown, the levels of endogenous anandamide are augmented further. When breakdown of anandamide is inhibited pharmacologically or genetically, anandamide is able to produce a state of intoxication similar to tetrahydrocannabinol in rodents and nonhuman primates (27–29). Thus, I suggest that chili peppers and vanilla were not chosen coincidentally or haphazardly as flavorings but precisely because, together, they were able to achieve high levels of anandamide.…”