A Comparison of the Discriminative Stimulus Effects of Δ⁹-Tetrahydrocannabinol and O-1812, a Potent and Metabolically Stable Anandamide Analog, in Rats.

Abstract

Efforts to determine whether Delta(9)-tetrahydrocannabinol (Delta(9)-THC) and anandamide elicit similar discriminative stimulus effects have yielded conflicting results. The difficulty in establishing a discriminative cue to anandamide may be due to its metabolic instability. Rats were trained to discriminate either Delta(9)-THC or O-1812, a metabolically stable anandamide analog, from vehicle to avoid this issue. O-1812 and Delta(9)-THC substituted for each other; however, both drugs were more potent in the O-1812-trained rats. Further, O-1812 only substituted for Delta(9)-THC at response rate decreasing doses. The CB(1) antagonist, SR141716A, blocked the discriminative stimulus effects of both drugs but augmented their rate effects. O-1839, a VR(1) agonist, failed to substitute for either cannabinoid. These results suggest that the discriminative stimulus effects of Delta(9)-THC and O-1812 are similar, but subtle differences also exist.

Discriminative stimulus effects of the cannabinoid CB1 receptor antagonist rimonabant in rats

“…Such an outcome is consistent with the idea that a cannabinoid CB 1 R agonist blocks the effects of a cannabinoid CB 1 R antagonist (see also McMahon 2006b) in much the same manner by which a CB 1 R agonist-induced discriminative stimulus is blocked by rimonabant in previous DD studies using operant methodology (De Vry and Jentzsch 2003;Järbe et al 2001Järbe et al , 2006aMansbach et al 1996;McMahon 2006a;Pério et al 1996;Wiley et al 1995Wiley et al , 2004 as well as DTA (Järbe et al 2004). Such antagonism, however, was not clearly extended to test conditions involving combinations of mAEA and (1) rimonabant (3 mg/kg) or (2) AM251 (5.6 mg/kg).…”

The Endogenous Cannabinoid Anandamide and Its Synthetic Analog R(+)-Methanandamide Are Intravenously Self-Administered by Squirrel Monkeys

“…Conversely, a short duration of effects favors demonstration of a high frequency of self-administered injections under FR10 selfadministration procedures (Ko et al, 2002). In addition, previous marked differences between behavioral effects of anandamide and those of its synthetic analogs methanandamide and O-1812 were found using the intraperitoneal route of administration (Romero et al, 1996;Jarbe et al, 2001;Wiley et al, 2004), whereas in this study, anandamide was delivered intravenously. It is possible that decreased hepatic first-passage metabolism with the intravenous route of administration greatly increased effects of anandamide but not methanandamide, which is resistant to metabolic inactivation by FAAH.…”

“…Also, anandamide still produces cannabimimetic effects in cannabinoid CB 1 receptor knock-out mice (Di Marzo et al, 2000b). Finally, anandamide does not generally produce THC-like responding in monkeys and rats in drug-discrimination studies, although its longer-lasting, metabolically stable, synthetic analogs R(ϩ)-methanandamide (methanandamide) (Abadji et al, 1994) and O-1812 [( R)-(20-cyano-16,16-dimethyl docosa-cis-5,8,11,14-tetraenoyl)-1Ј-hydroxy-2Ј-propylamine] do show cross-discrimination with low doses of THC in rats (Jarbe et al, 2001;Maldonado and Rodriguez de Fonseca, 2002;Tanda and Goldberg, 2003;Wiley et al, 2004), suggesting that difficulties in demonstrating THC-like behavioral effects of anandamide may be attributable to its rapid inactivation and short duration of action rather than to qualitative differences between anandamide and THC. Most of these observations contribute to expectations that various means of facilitating the actions of endogenous anandamide for therapeutic purposes (Piomelli, 2003(Piomelli, , 2004Di Marzo et al, 2004) would have minimal abuse liability, although there have been no reported attempts to assess reinforcing effects of anandamide directly, with the exception of one negative finding with intraperitoneal anandamide using a conditioned place preference procedure in rats (Mallet and Beninger, 1998).…”

Discriminative stimulus functions in rats of AM1346, a high-affinity CB1R selective anandamide analog

“…An emerging pattern appears to be that response rate following administration of CB 1 R agonists in rats is less amenable to antagonism by rimonabant, particularly rate changes associated with AEA and its analogs (Järbe et al 2003b;Wiley et al 2004). In addition, mAEA (but not Δ 9 -THC) decreased rates of responding that were not antagonized by rimonabant in CB 1 R-deficient mice (Baskfield et al 2004), indicating that these behavioral depressant effects of mAEA are not mediated by CB 1 R. Wiley et al (2005) also reported that the degree of cross-tolerance in mice between Δ 9 -THC on the one hand and AEA, 2-methylAEA and O-1812 on the other hand, varied with the test (locomotor activity, antinociception, temperature, and catalepsy) employed to examine cross-tolerance.…”