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The Journal of Neuroscience, May 1, 2003, 23(9):3916
Increased Seizure Susceptibility and Proconvulsant Activity of
Anandamide in Mice Lacking Fatty Acid Amide Hydrolase
Angela B.
Clement1,
E.
Gregory
Hawkins1,
Aron H.
Lichtman2, and
Benjamin F.
Cravatt1
1 The Skaggs Institute for Chemical Biology and
Departments of Cell Biology and Chemistry, The Scripps Research
Institute, La Jolla, California 92037, and 2 Department of
Pharmacology and Toxicology, Medical College of Virginia Campus,
Virginia Commonwealth University, Richmond, Virginia 23298
A number of recent in vitro studies have described a
role for endogenous cannabinoids ("endocannabinoids") as
transsynaptic modulators of neuronal activity in the hippocampus and
other brain regions. However, the impact that endocannabinoid signals
may have on activity-dependent neural events in vivo
remains mostly unknown and technically challenging to address because
of the short half-life of these chemical messengers in the
brain. Mice lacking the enzyme fatty acid amide hydrolase [FAAH
( /) mice] are severely impaired in their ability to degrade the
endocannabinoid anandamide and therefore represent a unique animal
model in which to examine the function of this signaling lipid
in vivo. Here, we show that the administration of
anandamide dramatically augments the severity of chemically induced
seizures in FAAH (/) mice but not in wild-type mice.
Anandamide-enhanced seizures in FAAH (/) mice resulted in
significant neuronal damage in the CA1 and CA3 regions of the
hippocampus for the bicuculline and kainate models, respectively.
Notably, in the absence of anandamide treatment, FAAH (/) mice
exhibited enhanced seizure responses to high doses of kainate that
correlated with greatly elevated endogenous levels of anandamide in the
hippocampus of these animals. Collectively, these studies suggest that
both exogenously administered and endogenously produced anandamide
display FAAH-regulated proconvulsant activity and do not support a
general neuroprotective role for this endocannabinoid in response to
excitotoxic stimuli in vivo. More generally, these findings demonstrate that the disinhibitory actions of endocannabinoids observed in hippocampal slices in vitro may also occur
in vivo.
Key words:
anandamide; bicuculline; CB1 receptor; endocannabinoid; epilepsy; excitotoxicity; fatty acid amide hydrolase; kainate; seizure
Copyright © 2003 Society for Neuroscience 0270-6474/03/2393916-08$05.00/0
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