Experiments are being conducted to assess the different neuropharmacological and behavioral mechanisms underlying behavior controlled by drugs as discriminative stimuli in rats and monkeys and the ability of pharmacological or behavioral manipulations to modify discrimination, as well as self-administration, of THC or nicotine, to disrupt ongoing food-maintained behavior to alter emotional responses such as anxiety or to modulate attention learning and memory processes. Currently, studies are focusing on nicotine and a series of cannabinoids, including delta-9-tetrahydrocannabinol (THC), the psychoactive ingredient in marijuana, the cannabinoid CB1 receptor antagonists Rimonabant and AM251, the endogenous cannabinoids anandamide and 2AG, the anandamide uptake inhibitor AM404, and the fatty acid amide hydrolase (FAAH) inhibitor URB597. Studies are also being conducted on methamphetamine, cocaine and heroin. Endocannabinoids are involved in a variety of behavioral and physiological processes that are just beginning to be understood. Inhibitors of fatty acid amide hydrolase (FAAH) increase endogenous levels of anandamide (a cannabinoid CB1-receptor ligand) and oleoylethanolamide and palmitoylethanolamide (OEA and PEA, ligands for a-type peroxisome proliferatoractivated nuclear receptors, PPAR- alpha) when and where they are naturally released in the brain. Using a passive-avoidance task in rats, we found that memory acquisition was enhanced by the FAAH inhibitor URB597 or by the PPAR-alpha agonist WY14643, and these enhancements were blocked by the PPAR- alpha antagonist MK886. These findings demonstrate novel mechanisms for memory enhancement by activation of PPAR- alpha, either directly by administering a PPAR- alpha agonist or indirectly by administering a FAAH inhibitor. In the five-choice serial reaction time task, exogenous cannabinoids have been found to alter attention, but endocannabinoids such as anandamide have not been studied. We used this task to evaluate the effects of anandamide in rats. Since anandamide is a ligand for not only cannabinoid receptors but also transient receptor potential vanilloid 1 (TRPV1) receptors, and as recently suggested, peroxisome proliferator-activated nuclear receptor- (PPAR), we also determined whether anandamides effects in this task were mediated by each of these receptors. Anandamide increased omission errors and decreased responding during inter-trial intervals. These effects were blocked by the TRPV1 antagonist capsazepine, but not by the cannabinoid-receptor antagonist rimonabant or the PPAR- alpha antagonist MK886. Testing with open-field activity and food-consumption procedures in the same rats suggested that the disruption of operant responding observed in the attention task was not due to motor depression, anxiety, decreased appetite, or an inability to find and consume food pellets. Thus, the vanilloid-dependent behavioral disruption induced by anandamide was specific to the operant attention task. These effects of anandamide resemble effects of systemically administered dopamine antagonists and might reflect changes in vanilloid-mediated dopamine transmission. The enzyme FAAH is a promising target for anxiety-related disorders. FAAH inhibitors (e.g., URB597) increase brain levels of anandamide and induce anxiolytic-like effects in rodents. Recent findings, however, questioned the efficacy of FAAH inhibitors as anxiolytics due to inconsistent findings in different labs. We tested here the hypothesis that conflicting findings are due to variations in the stressfulness of experimental conditions employed in various studies. We found that URB597 did not produce anxiolytic effects when the aversiveness of testing procedures was minimized by handling rats daily before experimentation, by habituating them to the experimental room, or by employing low illumination during testing. In contrast, URB597 had robust anxiolytic effects when the aversiveness of the testing environment was increased by eliminating habituation to the experimental room or by employing bright lighting conditions. Unlike URB597, the benzodiazepine chlordiazepoxide (5 mg/kg) had anxiolytic effects under all testing conditions. The anxiolytic effects of URB597 were abolished by the cannabinoid CB1-receptor antagonist AM251, showing that they were mediated by CB1 receptors. Our findings show that FAAH inhibition does not affect anxiety under mildly stressful circumstances but protects against the anxiogenic effects of aversive stimuli.
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