Differential Effects of Δ⁹-Tetrahydrocannabinol and Methanandamide in CB1 Knockout and Wild-Type Mice

Abstract

Mice devoid of CB1 cannabinoid receptors (CB1Ϫ/Ϫ mice) provide a unique opportunity to further investigate the role of CB1 receptors in exocannabinoid and endocannabinoid effects. CB1Ϫ/Ϫ mice (N ϭ 18) and their wild-type littermates (CB1ϩ/ϩ mice; N ϭ 12) were placed in standard mouse operant chambers and trained to lever press under a fixed ratio 10 schedule of reinforcement. When stable lever press responding under the fixed ratio 10 schedule had been established, cannabinoids and noncannabinoids were administered to both groups. CB1ϩ/ϩ mice acquired the lever press response more readily than CB1Ϫ/Ϫ mice. ⌬ 9 -Tetrahydrocannabinol (⌬ 9 -THC) decreased lever press responding in CB1ϩ/ϩ mice only, whereas methanandamide, a metabolically stable endocannabinoid analog, produced similar response rate decreases in both genotypic groups. Similar to ⌬ 9 -THC, another endocannabinoid analog, (R)- (20-cyano-16,16-dimethyl docosa-cis-5,8,11,14--THC, but not those of methanandamide. Because methanandamide binds poorly to CB2 receptors, these results suggest possible non-CB1, non-CB2 mechanisms of action for methanandamide-induced behavioral disruption of lever press responding. Ethanol and morphine elicited greater response decreases in CB1Ϫ/Ϫ mice than in CB1ϩ/ϩ mice, suggesting a possible role of CB1 receptors in the rate disruptive effects of these drugs. In contrast, diazepam did not produce between group differences, suggesting that CB1 receptors are not involved in diazepam-induced disruption of lever press responding. ⌬9 -Tetrahydrocannabinol (⌬ 9 -THC), the principle psychoactive constituent of marijuana and other natural, synthetic, and endocannabinoids, elicits a well characterized syndrome of pharmacological effects in laboratory animals (Dewey, 1986;Martin et al., 1991). These effects, including hypothermia, hypoactivity, antinociception, and catalepsy, are attributed mainly to the actions of cannabinoids at CB1 cannabinoid receptors in the brain (Martin et al., 1991). Recently, recombinant DNA techniques have made possible the development of CB1 receptor knockout mice (CB1Ϫ/Ϫ) Zimmer et al., 1999). These mice lack CB1 receptors and provide a unique opportunity to further investigate the role of these receptors in the pharmacological effects of cannabinoids. Research with CB1Ϫ/Ϫ mice demonstrates that the characteristic antinociceptive, hypoactive, and cataleptic effects of ⌬ 9 -THC are absent in these mice Di Marzo et al., 2000). Moreover, ⌬ 9 -THC stimulates [ 35 S]GTP␥S binding in brain membranes of CB1ϩ/ϩ mice, but not in those of CB1Ϫ/Ϫ mice (Di Marzo et al., 2000).Thus far, the measures examining the pharmacological effects of cannabinoids in CB1Ϫ/Ϫ mice, albeit important, represent unlearned responses. Previous research has demonstrated that cannabinoids, including ⌬ 9 -THC, WIN 55,212-2, and methanandamide, also disrupt performance in the Morris water maze, a working memory task (Varvel and Lichtman, 2002). The effects of cannabinoids on schedulecontrolled operant behavior have not been investiga...

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

“…Circling did not occur after mAEA administration (Järbe et al , 2003a. Similarly, mAEA rate decreases of lever pressing were also augmented by rimonabant, whereas such rate changes induced by Δ9-THC essentially were unaltered (Järbe et al 2003b; see also Baskfield et al 2004). To account for such findings, it has been suggested that cannabinoid ligands interact with CB 1 R/CB 2 R through different binding motifs and/or through non-CB 1 R/CB 2 R cellular targets including additional cannabinoid subtypes or cannabinoid-like receptors and involvement of vanilloid receptor (VR 1 ) mechanisms (Howlett 2004;Pacher et al 2006;Oz 2006 for reviews).…”

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

“…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. Although the neural mechanisms responsible for these varied effects are unclear, it is worth noting that vanilloid mechanism(s) do not seem important for the discriminative stimulus effects of CB 1 R agonists because (a) the TRPV1 antagonist capsazepine did not block the Δ 9 -THC-like effects of AEA (Solinas et al 2007a) and (b) the TRPV1 agonist O-1839 did not substitute for either Δ 9 -THC or O-1812 in rats discriminating between vehicle and either of these two CB 1 R agonists .…”

CB1 Receptor Knockout Mice Display Reduced Ethanol-Induced Conditioned Place Preference and Increased Striatal Dopamine D2 Receptors

“…Thus, studies have shown that the CB 1 receptor antagonist SR141716A reduces alcohol intake (Arnone et al, 1997;Colombo et al, 1998;Rodriguez de Fonseca et al, 1999) and the motivation to consume alcohol in a progressive ratio paradigm in rats, while a CB 1 receptor agonist increased the motivation to consume alcohol alcohol in a progressive ratio paradigm . In addition, ethanol (0.5-2.0 g/kg) has been shown to decrease operant responding to a greater extent in CB 1 À/À mice than in wild-type mice, suggesting a possible role of CB 1 receptor in the rate disruptive effects of ethanol (Baskfield et al, 2004). Recently, we and others have shown that ethanol consumption and/or preference are decreased in CB 1 À/À mice generated on a CD1 background (Naassila et al, 2004) or a C57BL/6J background (Poncelet et al, 2003).…”