Anandamide: The good and bad in epilepsy

Endogenous cannabinoid levels in the brain are relatively stable under typical physiological conditions, but in the epileptic brain, this signaling becomes altered on both short- and long-term time scales. Seizures result in a rapid and dramatic rise in anandamide (AEA), which likely contributes to seizure termination. Exogenous supplementation of AEA in seizure models has been found to reduce measures of excitability and promote antiseizure effects. Whereas fatty acid amide hydrolase (FAAH) inhibitors which prevent the enzymatic degradation of AEA and increase AEA's synaptic availability reduce seizure severity and protect against excitotoxic damage. However, following seizures, the rapid degradation of the large pool of AEA leads to a series of products such as arachidonic acid, prostaglandins, and prostanoids, which ultimately causes vasoconstriction leading to hypoperfusion and hypoxia that results in short-term behavioral dysfunction. Over the long term, seizure-induced stress responses mediated by corticosterone/cortisol also alters AEA involvement in network signaling leading to comorbid psychiatric disorders, which can include anxiety, fear impairment, and depression. Generally, boosting AEA levels (through FAAH inhibitors, direct supplementation, inhibition of AEA uptake, and metabolism) has been useful in ameliorating anxiety-like behaviors, fear memory impairments, and antidepressant effects. While antiseizure drugs effectively manage seizures for most people with epilepsy, it is an inadequate treatment and, in some cases, may worsen symptoms, for those who have behavioral comorbidities. Utilizing AEA treatments as a therapeutic target for epilepsy is an exciting area of research and holds great promise for the future treatment of this debilitating disease. This chapter focuses on our current understanding of both the positive and negative role of AEA in seizure disorders