The Endogenous Cannabinoid Anandamide Produces δ-9-Tetrahydrocannabinol-Like Discriminative and Neurochemical Effects That Are Enhanced by Inhibition of Fatty Acid Amide Hydrolase but Not by Inhibition of Anandamide Transport

Abstract

Anandamide is an endogenous ligand for brain cannabinoid CB 1 receptors, but its behavioral effects are difficult to measure due to rapid inactivation. Here we used a drug-discrimination procedure to test the hypothesis that anandamide, given i.v. or i.p., would produce discriminative effects like those of ␦-9-tetrahydrocannabinol (THC) in rats when its metabolic inactivation was inhibited. We also used an in vivo microdialysis procedure to investigate the effects of anandamide, given i.v. or i.p., on dopamine levels in the nucleus accumbens shell in rats. When injected i.v., methanandamide (AM-356), a metabolically stable anandamide analog, produced clear dose-related THC-like discriminative effects, but anandamide produced THC-like discriminative effects only at a high 10-mg/kg dose that almost eliminated lever-press responding. Cyclohexyl carbamic acid 3Ј-carbamoyl-biphenyl-3-yl ester (URB-597), an inhibitor of fatty acid amide hydrolase (FAAH), the main enzyme responsible for metabolic inactivation of anandamide, produced no THC-like discriminative effects alone but dramatically potentiated discriminative effects of anandamide, with 3 mg/kg anandamide completely substituting for the THC training dose. URB-597 also potentiated the ability of anandamide to increase dopamine levels in the accumbens shell. The THC-like discriminative-stimulus effects of anandamide after URB-597 and methanandamide were blocked by the CB 1 receptor antagonist rimonabant, but not the vanilloid VR 1 receptor antagonist capsazepine. Surprisingly, the anandamide transport inhibitors N-(4-hydroxyphenyl) 8,11, and N-(3-furylmethyl)eicosa-5,8,11,14-tetraenamide (UCM-707) did not potentiate THC-like discriminative effects of anandamide or its dopamine-elevating effects. Thus, anandamide has THC-like discriminative and neurochemical effects that are enhanced after treatment with a FAAH inhibitor but not after treatment with transport inhibitors, suggesting brain area specificity for FAAH versus transport/FAAH inactivation of anandamide.The endogenous cannabinoid (CB) system, which is targeted by the psychoactive ingredient in cannabis, ␦-9-tetrahydrocannabinol (THC), comprises receptors termed CB 1 and CB 2 (and others not yet identified) endogenous compounds that activate these receptors and enzymes involved in the synthesis and degradation of these endogenous cannabinoids

Modulation of the endocannabinoid system: Therapeutic potential against cocaine dependence

“…Rimonabant, however, did not affect the behavior maintained by cocaine when administered alone (140). In agreement with this report, Rimonabant pretreatment did not show any effect on cocaine self-administration under fixedratio schedules of behavior in squirrel monkeys (63), an effect that has been recently replicated and confirmed (141,142). In addition, Rimonabant did not affect the number of cocaine selfinjections in Wistar rats studied under a fixed-ratio 5 schedule of drug delivery (103,104).…”

“…Anandamide is then metabolized into the cell by an intracellular enzyme, the fatty acid amide hydrolase (FAAH) (60,61), the blockade of which has been shown to prolong the behavioral/neurobiological effects of anandamide (4,61,62,63). In contrast, 2-AG is metabolized through the mono glyceril lipase enzyme (54).…”

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

“…The outcomes of the antagonism tests are reminiscent of previous studies assessing surmountable antagonism of rimonabant by mAEA (Järbe et al 2001); animals ceased responding before full generalization (≥80% drug lever responding) might have been achieved (see also Solinas et al 2007). When agonist dose was held constant, i.e., the mAEA training dose, both rimonabant and AM251 (1 to 3 mg/kg) reduced mAEA (10 mg/ kg) appropriate responding to around 25% or lower, suggesting CB 1 R mediation for the DD effect; this was accompanied by a downward trend in response rate (Järbe et al 2006a).…”

“…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). Of these, vanilloid mechanism(s) do not appear important for cannabinoid DD, as the VR 1 antagonist capsazepine did not antagonize the Δ9-THC-like discriminative stimulus effects of anandamide (Solinas et al 2007), nor did the VR 1 agonist O-1839 substitute for DDs maintained by the CB 1 R agonists Δ9-THC and O-1812 (ACEA), a CB 1 R selective anandamide analog ). All of the above postulated mechanisms may, however, affect response rate.…”

Effects of Fatty Acid Amide Hydrolase (FAAH) Inhibitors in Non-Human Primate Models of Nicotine Reward and Relapse

“…The general procedure and apparatus have been described previously (Solinas et al, 2007). Rats were surgically implanted with a concentric dialysis probe aimed at the shell of the nucleus accumbens (2 mm anterior and 1.1 mm lateral from bregma, 8.0 mm below the dura) (Paxinos and Watson, 2005) under anesthesia.…”