Increased seizure susceptibility and proconvulsant activity of anandamide in mice lacking fatty acid amide hydrolase.
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.
The Skaggs Institute for Chemical Biology and Departments of Cell Biology and Chemistry, The Scripps Research Institute, La Jolla, California 92037, USA.
Angela B
AB
Clement
E Gregory
EG
Hawkins
Aron H
AH
Lichtman
Benjamin F
BF
Cravatt
D000581:Amidohydrolases / Q000172:deficiency* / Q000235:genetics; D000818:Animals; D001095:Arachidonic Acids / Q000633:toxicity*; D001640:Bicuculline; D063385:Cannabinoid Receptor Modulators; D003292:Convulsants / Q000633:toxicity*; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D004357:Drug Synergism; D063388:Endocannabinoids; D018756:GABA Antagonists; D020022:Genetic Predisposition to Disease; D006624:Hippocampus / Q000187:drug effects / Q000473:pathology; D007608:Kainic Acid; D008032:Limbic System / Q000187:drug effects / Q000473:pathology; D051379:Mice; D018345:Mice, Knockout; D009474:Neurons / Q000187:drug effects / Q000473:pathology; D009498:Neurotoxins; D053284:Polyunsaturated Alkamides; D012640:Seizures / Q000139:chemically induced / Q000201:enzymology / Q000503:physiopathology*; D000099252:Fatty Acid Amide Hydrolases
D000581:Amidohydrolases; D001095:Arachidonic Acids; D001640:Bicuculline; D063385:Cannabinoid Receptor Modulators; D003292:Convulsants; D063388:Endocannabinoids; D018756:GABA Antagonists; D007608:Kainic Acid; D009498:Neurotoxins; D053284:Polyunsaturated Alkamides; D000099252:Fatty Acid Amide Hydrolases; C078814:anandamide