Abstracts

RATIONALE: Previous work has indicated that the non-specific metabotropic glutamate receptor (mGluR) antagonist S-a-methyl-4-carboxyphenylglycine (MCPG) suppresses epileptiform activity produced by elevated potassium in the hippocampal slice (McBain, J. Neurophysiol. 1995). We evaluated the effect of selective mGluR receptor antagonists on epileptiform discharges produced by elevated extracellular potassium ([K⁺][sub]o[/sub]).
METHODS: Hippocampal slices were prepared from young adult rats and exposed to an artificial cerebrospinal fluid with a [K⁺][sub]o[/sub] of 7.5 mM. Extracellular recordings were made in the CA3 region to monitor spontaneously occurring epileptiform discharges. The rate of discharges was determined and changes produced by MCPG, 7-(hydroxyimino)cyclopropa[b]chromen-1a-carboxylate ethyl ester (CPCCOEt , a mGluR1 antagonist), LY367385 (a mGluR1 antagonist), 2-methyl-6-(phenylethynyl)pyridine (MPEP, a mGluR5 antagonist), and LY341495 (mGluR2 and 3 antagonist at concentrations less than 100 nM) were assessed.
RESULTS: MCPG (250 [mu]M) decreased the rate of high [K⁺][sub]o[/sub] epileptiform discharges from 0.37 [plusminus] 0.05 to 0.175 [plusminus] 0.07 Hz (P [lt] 0.05, n = 43). Neither the selective mGluR1 antagonist CPCCOEt (30 [mu]M) nor the selective mGluR5 antagonist MPEP (10 [mu]M) changed the rate of discharges. Co-application of both mGluR1 and 5 non-competitive antagonists (100 [mu]M CPCCOEt and MPEP) actually increased the rate of discharges from 0.16 [plusminus] 0.05 to 0.26 [plusminus] 0.07 Hz (p [lt] 0.05, n = 5). The competitive mGluR1 antagonist LY367385 depressed the rate of discharges at concentrations greater than 3 [mu]M (0.38 [plusminus] 0.05 vs. 0.21 [plusminus] 0.04 Hz, p [lt] 0.05, n=28). The selective Group II antagonist LY341495 (10 nM) stopped discharges in 8 of 10 slices with 30 nM stopping the discharges in the two slices that continued to have spontaneous activity
CONCLUSIONS: Group I agonists produce epileptiform activity in the hippocampal slice and we expected the suppression of high [K⁺][sub]o[/sub] discharges by MCPG to be a result of group I antagonism. Surprisingly selective mGluR1 or 5 non-competitve antagonists did not alter the rate of high [K⁺][sub]o[/sub] epileptiform discharges, although the competitive mGluR1 antagonist LY367385 depressed the discharge rate. Group II mGluR antagonism suppressed discharges completely. These results suggest that elevation in [K⁺][sub]o[/sub] activates mGluR1 and group II mGluR and that these receptors contribute to the generation of high [K⁺][sub]o[/sub]-induced epileptiform discharges.
[Supported by: Veterans Administration Research]; (Disclosure: Salary - Veterans Adminstration, Grant - Veterans Adminstration)