DHPG-INDUCED BEHAVIORAL SYNDROME IN MICE
Abstract number :
2.109
Submission category :
Year :
2003
Submission ID :
2076
Source :
www.aesnet.org
Presentation date :
12/6/2003 12:00:00 AM
Published date :
Dec 1, 2003, 06:00 AM
Authors :
Matthew E. Barton, Lijuan Yang, Harlan E. Shannon Lilly Research Laboratories, Eli Lilly and Company, Indianapolis, IN
Several lines of evidence point to involvement of group I metabotropic glutamate receptors in seizures. For example, the mGlu1 and mGlu5 receptor antagonists LY456236 and MPEP, respectively, were shown to be anticonvulsant in the 6 Hz model of partial seizures. Furthermore, i.c.v. administration of the group I selective agonists 3,5 DHPG and 1S,3R-ACPD produced dose-dependent increases in limbic seizures. The present investigation was designed to examine the potential role of mGlu1 receptors in seizures by using the mGlu1 receptor preferring agonist (S) 3,5 DHPG.
Varying doses of (S) 3,5 DHPG (10 [ndash] 400 nmol) were administered (i.c.v.) to male CD-1 mice. An arbitrary score of 1 was assigned to each animal for each of the following behaviors observed: tremors, scratching and/or facial grooming, forelimb clonus, rearing, and falling. Separate groups of animals were pretreated with mGlu1, mGlu5, and non-NMDA receptor antagonists prior to the DHPG challenge.
Previous studies have demonstrated that DHPG produced seizures in a dose-dependent manner and was sensitive to block by dantrolene, L-AP3, L-AP4, L-SOP, and L-CCGI and insensitive to the ionotropic glutamate receptor antagonists MK-801 and GYKI 52466. In the present study, DHPG was observed to produce a behavioral syndrome with characteristics marked by immobility, tremors, scratching and/or facial grooming, low frequency ([lt] 1 Hz) forelimb clonus, rearing, and falling. The mGlu1 selective antagonist LY456236 lessened the severity of the DHPG-induced syndrome while the mGlu5 antagonist MPEP had no effect in reducing behavioral score. In contrast to earlier reports however, the non-NMDA antagonists GYKI 52466 and NBQX decreased the behavioral score.
This investigation suggests that DHPG-induced behavioral syndrome is not likely due solely to mGlu1 receptor activation and may be due, in part to non-NMDA receptor activity. Ongoing studies are attempting to examine the effect of DHPG on surface EEG recordings in the rat.
[Supported by: Eli Lilly and Company.]