Abstract
Recent reports have demonstrated that disruption of CB1 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 CB1 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 CB1 receptor mechanism of action. In contrast, the primary psychoactive constituent of marijuana, Δ9-tetrahydrocannabinol, failed to affect extinction rates, suggesting that FAAH is a more effective target than a direct acting CB1 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.
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Acknowledgements
This work was supported by NIDA Grants DA015683, DA017259, DA005274, and T23DA07027. The authors are very grateful for the guidance and suggestions of Dr Billy R Martin.
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Varvel, S., Wise, L., Niyuhire, F. et al. Inhibition of Fatty-Acid Amide Hydrolase Accelerates Acquisition and Extinction Rates in a Spatial Memory Task. Neuropsychopharmacol 32, 1032–1041 (2007). https://doi.org/10.1038/sj.npp.1301224
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DOI: https://doi.org/10.1038/sj.npp.1301224
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