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Inhibition of fatty-acid amide hydrolase accelerates acquisition and extinction rates in a spatial memory task.
Neuropsychopharmacology. 2007 May; 32(5):1032-41.N

Abstract

Recent reports have demonstrated that disruption of CB(1) receptor signaling impairs extinction of learned responses in conditioned fear and Morris water maze paradigms. Here, we test the hypothesis that elevating brain levels of the endogenous cannabinoid anandamide through either genetic deletion or pharmacological inhibition of its primary catabolic enzyme fatty-acid amide hydrolase (FAAH) will potentiate extinction in a fixed platform water maze task. FAAH (-/-) mice and mice treated with the FAAH inhibitor OL-135, did not display any memory impairment or motor disruption, but did exhibit a significant increase in the rate of extinction. Unexpectedly, FAAH-compromised mice also exhibited a significant increase in acquisition rate. The CB(1) receptor antagonist SR141716 (rimonabant) when given alone had no effects on acquisition, but disrupted extinction. Additionally, SR141716 blocked the effects of OL-135 on both acquisition and extinction. Collectively, these results indicate that endogenous anandamide plays a facilitatory role in extinction through a CB(1) receptor mechanism of action. In contrast, the primary psychoactive constituent of marijuana, Delta(9)-tetrahydrocannabinol, failed to affect extinction rates, suggesting that FAAH is a more effective target than a direct acting CB(1) receptor agonist in facilitating extinction. More generally, these findings suggest that FAAH inhibition represents a promising pharmacological approach to treat psychopathologies hallmarked by an inability to extinguish maladaptive behaviors, such as post-traumatic stress syndrome and obsessive-compulsive disorder.

Authors+Show Affiliations

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

Pub Type(s)

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

Language

eng

PubMed ID

17047668

Citation

Varvel, Stephen A., et al. "Inhibition of Fatty-acid Amide Hydrolase Accelerates Acquisition and Extinction Rates in a Spatial Memory Task." Neuropsychopharmacology : Official Publication of the American College of Neuropsychopharmacology, vol. 32, no. 5, 2007, pp. 1032-41.
Varvel SA, Wise LE, Niyuhire F, et al. Inhibition of fatty-acid amide hydrolase accelerates acquisition and extinction rates in a spatial memory task. Neuropsychopharmacology. 2007;32(5):1032-41.
Varvel, S. A., Wise, L. E., Niyuhire, F., Cravatt, B. F., & Lichtman, A. H. (2007). Inhibition of fatty-acid amide hydrolase accelerates acquisition and extinction rates in a spatial memory task. Neuropsychopharmacology : Official Publication of the American College of Neuropsychopharmacology, 32(5), 1032-41.
Varvel SA, et al. Inhibition of Fatty-acid Amide Hydrolase Accelerates Acquisition and Extinction Rates in a Spatial Memory Task. Neuropsychopharmacology. 2007;32(5):1032-41. PubMed PMID: 17047668.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Inhibition of fatty-acid amide hydrolase accelerates acquisition and extinction rates in a spatial memory task. AU - Varvel,Stephen A, AU - Wise,Laura E, AU - Niyuhire,Floride, AU - Cravatt,Benjamin F, AU - Lichtman,Aron H, Y1 - 2006/10/18/ PY - 2006/10/19/pubmed PY - 2007/6/6/medline PY - 2006/10/19/entrez SP - 1032 EP - 41 JF - Neuropsychopharmacology : official publication of the American College of Neuropsychopharmacology JO - Neuropsychopharmacology VL - 32 IS - 5 N2 - Recent reports have demonstrated that disruption of CB(1) receptor signaling impairs extinction of learned responses in conditioned fear and Morris water maze paradigms. Here, we test the hypothesis that elevating brain levels of the endogenous cannabinoid anandamide through either genetic deletion or pharmacological inhibition of its primary catabolic enzyme fatty-acid amide hydrolase (FAAH) will potentiate extinction in a fixed platform water maze task. FAAH (-/-) mice and mice treated with the FAAH inhibitor OL-135, did not display any memory impairment or motor disruption, but did exhibit a significant increase in the rate of extinction. Unexpectedly, FAAH-compromised mice also exhibited a significant increase in acquisition rate. The CB(1) receptor antagonist SR141716 (rimonabant) when given alone had no effects on acquisition, but disrupted extinction. Additionally, SR141716 blocked the effects of OL-135 on both acquisition and extinction. Collectively, these results indicate that endogenous anandamide plays a facilitatory role in extinction through a CB(1) receptor mechanism of action. In contrast, the primary psychoactive constituent of marijuana, Delta(9)-tetrahydrocannabinol, failed to affect extinction rates, suggesting that FAAH is a more effective target than a direct acting CB(1) receptor agonist in facilitating extinction. More generally, these findings suggest that FAAH inhibition represents a promising pharmacological approach to treat psychopathologies hallmarked by an inability to extinguish maladaptive behaviors, such as post-traumatic stress syndrome and obsessive-compulsive disorder. SN - 0893-133X UR - https://www.unboundmedicine.com/medline/citation/17047668/Inhibition_of_fatty_acid_amide_hydrolase_accelerates_acquisition_and_extinction_rates_in_a_spatial_memory_task_ L2 - http://dx.doi.org/10.1038/sj.npp.1301224 DB - PRIME DP - Unbound Medicine ER -