Title

Epileptiform activity in the CA1 region of the hippocampus becomes refractory to attenuation by cannabinoids in part due to endogenous GABAB activity

Date of Completion

January 2010

Keywords

Health Sciences, Pharmacology|Biology, Neurobiology|Biology, Physiology

Degree

Ph.D.

Abstract

Marijuana has been anecdotally recognized as an anticonvulsant drug for centuries, yet its clinical use has been limited by its psychoactive effects. The active constituents of marijuana are known as cannabinoids, and their target in the central nervous system is the Gi/o coupled cannabinoid receptor type I (CB1R). The CB1R, its endogenous ligands (the endocannabinoids, eCBs), and the synthetic and metabolic enzymes for eCBs comprise the endocannabinoid system (eCB system). The eCB system is a promising therapeutic target for the treatment of epilepsy. In many animal models of epilepsy, cannabinoid agonists are anticonvulsant. Further, cannabinoid receptor antagonists can exacerbate seizures in rodents and humans, reinforcing the possible protective role of endogenous cannabinoids. However, in some animal studies, cannabinoid agonists demonstrate no effect or even a proconvulsant effect, complicating the introduction of cannabinoid therapeutics for use in humans. The mechanisms underlying the mixed efficacy of cannabinoids during seizures are poorly understood. The CB1R is highly expressed at the presynaptic terminals of a subclass of inhibitory interneurons, where its activation inhibits GABA release. CB1R activation at presynaptic glutamatergic terminals also decreases glutamate release. The opposing effects of the eCB system on inhibitory and excitatory neurotransmission may explain the conflicting effects of cannabinoid agonists in epilepsy. However, this potential mechanism has not been well evaluated. The overall goal of my work is to examine the anticonvulsant potential of the endogenous cannabinoid system. I utilized field potential recordings in the hippocampus and a variety of models of in vitro epileptiform activity to determine how cannabinoid agonists exert their anticonvulsant effects, the factors that determine the antiepileptiform efficacy of cannabinoids, and the protective role of the eCB system during seizures. ^