Abnormalities in 5-HT2C Receptor Binding in Severe Seizure Genetically Epilepsy-Prone Rats (GEPR-9).
Abstract number :
3.250
Submission category :
Year :
2000
Submission ID :
723
Source :
www.aesnet.org
Presentation date :
12/2/2000 12:00:00 AM
Published date :
Dec 1, 2000, 06:00 AM
Authors :
Ronald A Browning, Michelle A Merrill, Todd M Shaw, John W Dailey, Phillip C Jobe, Southern Illinois Univ Sch Med, Carbondale, IL; Univ of Illinois Coll of Medicine, Peoria, IL.
Rationale: There is an inverse relationship between serotonin (5-HT) brain levels and the severity of audiogenic seizures (AGS) in the GEPR. GEPRs are deficient in several presynaptic markers of 5-HT neurons, but also have abnormalities in their 5-HT1A and 5-HT1B receptors. In light of findings suggesting that the 5-HT2C receptor is an important regulator of AGS susceptibility, it was of interest to determine if there are abnormalities in the 5-HT2C receptor in the GEPR brain. Methods: 3H-Mesulergine (5-HT2C antagonist) binding was assessed in membranes prepared from cerebral cortex, hippocampus, midbrain, corpra quadrigemina, and pons-medulla of age-matched, seizure experienced female GEPR-9s and non-epileptic controls (NEC). Membranes were incubated with 3H-mesulergine (0.25 - 10 nM) for 10 min and the reaction was terminated by rapid filtration. Unlabeled spiperone (20 nM) was present in all tubes to prevent mesulergine binding to 5-HT2A receptors and unlabeled 5-HT (20 ?M) was present in alternate tubes to assess specific binding. Results: The Bmax and Kd for 3H-mesulergine binding to 5-HT2C receptors were significantly reduced in cerebral cortex membranes of GEPR-9s when compared to NEC rats. However, the Bmax for 5-HT2C receptor binding was significantly increased, while the Kd was unchanged in the midbrain and pons-medulla of GEPR-9s as compared to NECs. The hippocampus and corpra quadrigemina failed to display any differences in binding between GEPRs and NECs. Discussion: These findings show GEPR-9s have a deficit in the number of 5-HT2C receptors in the cortex, but have an increase in the number of 5-HT2C receptors in the brainstem (midbrain and pons-medulla). Inasmuch as the AGS in GEPRs is a brainstem-driven seizure that is inhibited by 5-HT2C agonists, it seems unlikely that the increased receptor binding in the brainstem of GEPRs contributes to the seizure-prone state in these animals. However, it is possible that this represents up-regulation of 5-HT2C receptors as a consequence of the deficit in 5-HT levels. Alternatively, the increased 5-HT2C Bmax may represent an attempt to compensate for the seizure prone state of the GEPR brainstem.