RT Journal Article
SR Electronic
T1 Increased Seizure Susceptibility and Proconvulsant Activity of Anandamide in Mice Lacking Fatty Acid Amide Hydrolase
JF The Journal of Neuroscience
JO J. Neurosci.
FD Society for Neuroscience
SP 3916
OP 3923
DO 10.1523/JNEUROSCI.23-09-03916.2003
VO 23
IS 9
A1 Angela B. Clement
A1 E. Gregory Hawkins
A1 Aron H. Lichtman
A1 Benjamin F. Cravatt
YR 2003
UL http://www.jneurosci.org/content/23/9/3916.abstract
AB 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 vivoremains 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 lipidin 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 occurin vivo.