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Vol. 302, Issue 1, 73-79, July 2002
The Skaggs Institute for Chemical Biology and Departments of Cell
Biology and Chemistry, The Scripps Research Institute, La Jolla,
California (G.H., B.F.C.); and Department of Pharmacology and
Toxicology, Medical College of Virginia Campus, Virginia Commonwealth
University, Richmond, Virginia (A.H.L., G.G.)
Fatty acid amides (FAAs) represent a class of neuromodulatory lipids
that includes the endocannabinoid anandamide and the sleep-inducing
substance oleamide. Both anandamide and oleamide produce behavioral
effects indicative of cannabinoid activity, but only anandamide binds
the cannabinoid (CB1) receptor in vitro. Accordingly, oleamide has been
proposed to induce its behavioral effects by serving as a competitive
substrate for the brain enzyme fatty acid amide hydrolase (FAAH) and
inhibiting the degradation of endogenous anandamide. To test the role
that FAAH plays as a mediator of oleamide activity in vivo, we have
compared the behavioral effects of this FAA in FAAH(+/+) and (
/)
mice. In both genotypes, oleamide produced hypomotility, hypothermia,
and ptosis, all of which were enhanced in FAAH(/) mice, were
unaffected by the CB1 antagonist
N-(piperidin-1-yl)-5-(4-chlorophenyl)-1-(2,4-di-chlorophenyl)-4-methyl-1H-pyrazole-3-carboxamide hydrochloride (SR141716A) and occurred in CB1(/) mice.
Additionally, oleamide displayed negligible binding to the CB1 receptor
in brain extracts from either FAAH(+/+) or (/) mice. In contrast,
anandamide exhibited a 15-fold increase in apparent affinity for the
CB1 receptor in brains from FAAH(/) mice, consistent with its
pronounced CB1-dependent behavioral effects in these animals. Contrary
to both oleamide and anandamide, monoacylglycerol lipids exhibited equivalent hydrolytic stability and pharmacological activity in FAAH(+/+) and (/) mice. Collectively, these results indicate that
FAAH is a key regulator, but not mediator of FAA activity in vivo. More
generally, these findings suggest that FAAs represent a family of
signaling lipids that, despite sharing similar chemical structures and
a common pathway for catabolism, produce their behavioral effects
through distinct receptor systems in vivo.
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