LONG TERM PLASTICITY CHANGES IN THE EXPRESSION OF THE CANNABINOID RECEPTOR IS ASSOCIATED WITH EPILEPTOGENESIS AND REGULATION OF SEIZURE FREQUENCY AND DURATION IN THE PILOCARPINE MODEL OF EPILEPSY
Abstract number :
1.077
Submission category :
Year :
2003
Submission ID :
534
Source :
www.aesnet.org
Presentation date :
12/6/2003 12:00:00 AM
Published date :
Dec 1, 2003, 06:00 AM
Authors :
Robert Blair, Lisa Wallice, Katherine Falenski, Billy Martin, Robert DeLorenzo Neurology, Virginia Commonwealth University, Richmond, VA; Pharmacology and Toxicology, Virginia Commonwealth University, Richmond, VA; Molecular Biophysics and Biochemistry, V
Cannabinoids are known to have anticonvulsant properties and recent studies have demonstrated that the anticonvulsant effects of cannabinoids and endocannabinoids are mediated through the activation of the cannabinoid 1 (CB1) receptor, the most highly expressed G-protien coupled receptor in the brain (Eur. J. Pharmacol. 2001;428:52; Eur. J. Pharmacol. 2002;452:295). However, little is known concerning the role of the CB1 receptor in regulating seizure discharge in epilepsy. This study was initiated to investigate the endogenous role of the CB1 receptor in the pilocarpine model of epilepsy.
Epilepsy was caused in rats using the pilocarpine model (Brain Res. 2001;903:1). The effects of cannabinoid agonists and antagonists on seizure frequency and duration were determined using video EEG monitoring of the epileptic animals. Cannabinoid agonists and antagonists were administered by intraperitoneal injection. Western blot and immunohistochemical analyses were used to evaluate hippocampal CB1 protein expression from control and epileptic tissue. The anatomical distribution of the CB1 receptor in control and epileptic brains was studied using immunohistochemical staining of the CB1 receptor protein on coronal sections. In addition, acute seizures were shown to increase levels of endogenous cannabinoids, demonstrating a possible physiological role for these agents in modulating seizure expression.
The marijuana extract, delta9-tetrahydrocannabinol (THC) and other cannabinoid agonists completely abolished spontaneous seizure activity in the epileptic animals. Administration of the CB1 receptor antagonist, SR141716A, significantly increased both seizure duration and frequency. Moreover, CB1 receptor antagonism in some animals induced prolonged electrographic and behavioral seizures that met the definition of status epilepticus. Western blot and immunohistochemical studies on control and epileptic tissue showed that epression of CB1 receptor protein was significantly increased in the epileptic hippocampus.
By elucidating a role for the endogenous cannabinoid system in regulating seizure activity, the results from this study illustrate a function for the endogenous cannabinoid system in modulating seizure frequency and duration in epileptic animals and suggest that inhibition of the CB1 receptor may play a role in the development of status epilepticus. The long term plasticity changes in expression of the CB1 receptor in association with epileptogenesis further suggest a major role for the endogenous cannabinoid system in epileptogenesis.
[Supported by: NIH-NINDS Grant R01NS23350 and P50NS25630 to RD and NIDA Grant P50DA05274 to RD and BM.]