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Fatty acid amide hydrolase (-/-) mice exhibit an increased sensitivity to the disruptive effects of anandamide or oleamide in a working memory water maze task.
J Pharmacol Exp Ther. 2006 Apr; 317(1):251-7.JP

Abstract

Although recent evidence suggests that fatty acid amide hydrolase (FAAH) may represent a potential therapeutic target, few published studies have investigated FAAH or its fatty acid amide substrates (FAAs) in animal models of learning and memory. Therefore, our primary goal was to determine whether FAAH (-/-) mice, which possess elevated levels of anandamide and other FAAs, would display altered performance in four Morris water maze tasks: acquisition of a hidden fixed platform, reversal learning, working memory, and probe trials. FAAH (-/-) mice failed to exhibit deficits in any task; in fact, they initially acquired the working memory task more rapidly than FAAH (+/+) mice. The second goal of this study was to investigate whether the FAAH inhibitor OL-135 (1-oxo-1[5-(2-pyridyl)-2-yl]-7-phenylheptane), anandamide, other FAAs, and methanandamide would affect working memory in both genotypes. FAAH (-/-), but not (+/+), mice displayed working memory impairments following exogenous administration of anandamide (ED(50) = 6 mg/kg) or oleamide (50 mg/kg). However, the central cannabinoid receptor (CB(1)) receptor antagonist SR141716 [N-(piperidin-1-yl)-5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4-methyl-1H-pyrazole-3-carboxamide HCl] only blocked the disruptive effects of anandamide. Methanandamide, which is not metabolized by FAAH, disrupted working memory performance in both genotypes (ED(50) = 10 mg/kg), suggesting that CB(1) receptor signaling is unaltered by FAAH deletion. In contrast, OL-135 and other FAAs failed to affect working memory in either genotype. These results suggest that FAAH deletion does not impair spatial learning but may enhance acquisition under certain conditions. More generally, FAAH may represent a novel therapeutic target that circumvents the undesirable cognitive side effects commonly associated with direct-acting cannabinoid agonists.

Authors+Show Affiliations

Department of Pharmacology and Toxicology, Medical College of Virginia Campus, Virginia Commonwealth University, Richmond, 23298-0613, USA.No affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Journal Article
Research Support, N.I.H., Extramural

Language

eng

PubMed ID

16352706

Citation

Varvel, Stephen A., et al. "Fatty Acid Amide Hydrolase (-/-) Mice Exhibit an Increased Sensitivity to the Disruptive Effects of Anandamide or Oleamide in a Working Memory Water Maze Task." The Journal of Pharmacology and Experimental Therapeutics, vol. 317, no. 1, 2006, pp. 251-7.
Varvel SA, Cravatt BF, Engram AE, et al. Fatty acid amide hydrolase (-/-) mice exhibit an increased sensitivity to the disruptive effects of anandamide or oleamide in a working memory water maze task. J Pharmacol Exp Ther. 2006;317(1):251-7.
Varvel, S. A., Cravatt, B. F., Engram, A. E., & Lichtman, A. H. (2006). Fatty acid amide hydrolase (-/-) mice exhibit an increased sensitivity to the disruptive effects of anandamide or oleamide in a working memory water maze task. The Journal of Pharmacology and Experimental Therapeutics, 317(1), 251-7.
Varvel SA, et al. Fatty Acid Amide Hydrolase (-/-) Mice Exhibit an Increased Sensitivity to the Disruptive Effects of Anandamide or Oleamide in a Working Memory Water Maze Task. J Pharmacol Exp Ther. 2006;317(1):251-7. PubMed PMID: 16352706.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Fatty acid amide hydrolase (-/-) mice exhibit an increased sensitivity to the disruptive effects of anandamide or oleamide in a working memory water maze task. AU - Varvel,Stephen A, AU - Cravatt,Benjamin F, AU - Engram,April E, AU - Lichtman,Aron H, Y1 - 2005/12/13/ PY - 2005/12/15/pubmed PY - 2006/5/26/medline PY - 2005/12/15/entrez SP - 251 EP - 7 JF - The Journal of pharmacology and experimental therapeutics JO - J. Pharmacol. Exp. Ther. VL - 317 IS - 1 N2 - Although recent evidence suggests that fatty acid amide hydrolase (FAAH) may represent a potential therapeutic target, few published studies have investigated FAAH or its fatty acid amide substrates (FAAs) in animal models of learning and memory. Therefore, our primary goal was to determine whether FAAH (-/-) mice, which possess elevated levels of anandamide and other FAAs, would display altered performance in four Morris water maze tasks: acquisition of a hidden fixed platform, reversal learning, working memory, and probe trials. FAAH (-/-) mice failed to exhibit deficits in any task; in fact, they initially acquired the working memory task more rapidly than FAAH (+/+) mice. The second goal of this study was to investigate whether the FAAH inhibitor OL-135 (1-oxo-1[5-(2-pyridyl)-2-yl]-7-phenylheptane), anandamide, other FAAs, and methanandamide would affect working memory in both genotypes. FAAH (-/-), but not (+/+), mice displayed working memory impairments following exogenous administration of anandamide (ED(50) = 6 mg/kg) or oleamide (50 mg/kg). However, the central cannabinoid receptor (CB(1)) receptor antagonist SR141716 [N-(piperidin-1-yl)-5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4-methyl-1H-pyrazole-3-carboxamide HCl] only blocked the disruptive effects of anandamide. Methanandamide, which is not metabolized by FAAH, disrupted working memory performance in both genotypes (ED(50) = 10 mg/kg), suggesting that CB(1) receptor signaling is unaltered by FAAH deletion. In contrast, OL-135 and other FAAs failed to affect working memory in either genotype. These results suggest that FAAH deletion does not impair spatial learning but may enhance acquisition under certain conditions. More generally, FAAH may represent a novel therapeutic target that circumvents the undesirable cognitive side effects commonly associated with direct-acting cannabinoid agonists. SN - 0022-3565 UR - https://www.unboundmedicine.com/medline/citation/16352706/Fatty_acid_amide_hydrolase___/___mice_exhibit_an_increased_sensitivity_to_the_disruptive_effects_of_anandamide_or_oleamide_in_a_working_memory_water_maze_task_ L2 - http://jpet.aspetjournals.org/cgi/pmidlookup?view=long&pmid=16352706 DB - PRIME DP - Unbound Medicine ER -