Functional Redistribution of Hippocampal Cannabinoid Cb1 Receptors in the Rat Pilocarpine Model of Acquired Epilepsy

FUNCTIONAL REDISTRIBUTION OF HIPPOCAMPAL CANNABINOID CB1 RECEPTORS IN THE RAT PILOCARPINE MODEL OF ACQUIRED EPILEPSY Katherine W. Falenski, B.S. A dissertation submitted in partial fulfillment of the requirements for the degree of Doctor of Philosophy at Virginia Commonwealth University. Virginia Commonwealth University, 2006 Director: Dr. Robert J. DeLorenzo, M.D., Ph.D., M.P.H George Bliley Professor Department of Neurology Cannabinoids, such as the marijuana derivative a9-THC, are known to have CBI receptor-mediated anticonvulsant effects in several animal models of seizures and epilepsy, including the rat pilocarpine model of acquired epilepsy. However, the distribution of CBI receptor expression and function in brains of epileptic rats has not been characterized. Therefore, this dissertation was initiated to evaluate the effect of epileptogenesis on the distribution and function of the endogenous CBI receptor system in the rat pilocarpine model, a well-established model of acquired temporal lobe epilepsy. xvi Using in~munohistochemistry, we demonstrated that chronically epileptic rats exhibit a unique, long-term, and specific redistribution of hippocampal CBl receptors when compared to controls, with concurrent layer-specific increases and decreases in CB1 receptor expression within the hippocampus. In addition, studies in this dissertation demonstrated using ['HI WIN^ 5,2 12-2 autoradiography and agonist-stimulated ['"IGTP~S autoradiography that this CB1 receptor-specific reorganization results in corresponding functional changes manifested by alterations in CB1 receptor binding and G-protein activation. These regionally selective changes were dependent on NMDA receptor activation during the initial insult of pilocarpine-induced status epilepticus (SE), and were independent of seizure suppression produced with phenobarbital administration in epileptic rats. Furthermore, time-course studies utilizing these techniques demonstrate that within a week following SE, a widespread loss of CB1 receptor expression and function occurs throughout the hippocampus. The subsequent redistribution of CB1 receptors that occurs temporally correlates with the emergence of spontaneous recurrent seizures, and is still observed up to 1 year following SE. Overall, the reorganization of cannabinoid receptors in epilepsy implicates the endocannabinoid system in modulating neuroexcitability in the epileptic state. This CBl receptor redistribution represents an essentially permanent neuronal plasticity change associated with epileptogenesis, and could account for the anticonvulsant effect of cannabinoids observed in this model.