Effects of subtype-selective group I mGluR antagonists on synchronous activity induced by 4-aminopyridine/CGP 55845 in adult guinea pig hippocampal slices.

Co-application of the convulsant 4-aminopyridine (4-AP) and the GABA(B) receptor antagonist CGP 55845 to adult guinea pig hippocampal slices elicits giant GABA-mediated postsynaptic potentials (GPSPs) and epileptiform discharges. Here we tested the effects of the group I metabotropic glutamate receptor (mGluR) subtype-selective antagonists LY 367385 (mGlu1, 100 microM), MPEP (mGlu5, 10 microM), and MTEP (mGlu5, 500 nM) on this synchronous activity. Electrophysiological field recordings were performed in the CA3 region of hippocampal slices from adult guinea pigs. The mGlu5 receptor antagonists increased GPSP rate, but the mGlu1 receptor antagonist did not. This ability of mGlu5 receptor antagonists to increase the rate of GPSPs indicates that enough endogenous glutamate is released under these conditions to activate group I mGluR; nevertheless, co-application of a mGlu1 receptor antagonist (LY 367385 or JNJ 16259685) and MPEP did not decrease pre-existing epileptiform activity. Furthermore, co-application of LY 367,385 and MPEP did not prevent the emergence of epileptiform activity. When ionotropic glutamate receptor (iGluR) antagonists were present, neither MPEP nor the group I mGluR agonist DHPG changed GPSP rate, suggesting that pyramidal cell-to-interneuron iGluR-mediated synaptic connections are involved in the rate change mechanism. In contrast to the lack of effect of group I mGluR antagonists on epileptiform activity in the 4-AP/CGP 55845 model, group I mGluR antagonists blocked the emergence of longer epileptiform events and decreased the overall amount of synchronous activity in the GABA(A) antagonist/4-AP model. In conclusion, in the 4-AP/CGP 55845 model, enough glutamate was released to activate group I mGluRs and affect GPSP rate via mGlu5 receptors; however, this group I mGluR activation was not required for the generation of the epileptiform activity.