THE POTENT NON-COMPETITIVE MGLU1 RECEPTOR ANTAGONIST BAY 36-7620 DIFFERENTIALLY AFFECTS SYNAPTIC PLASTICITY IN AREA CORNU AMMONIS 1 OF RAT HIPPOCAMPAL SLICES AND IMPAIRS ACQUISITION IN THE WATER MAZE TASK IN MICE

摘要

In this study we evaluated the effects of the novel, potent non-competitive metabotropic glutamate receptor (mGluR) 1 antagonist (3aS,6aS)-6a-naphthalen-2-ylmethyl-5-methyliden-hexahydro-cyclopental[c]furan-1-on (BAY 36-7620) on different types of synaptic plasticity in the hippocampal cornu ammonis (CA) 1-region and on hippocampus-dependent spatial learning. After having confirmed the presence of mGluR1 in the hippocampal CA1 region of our rat strain by confocal microscopy, we tested the effects of BAY 36-7620 on: 1) long-term potentiation (LTP) induced, by weak and strong stimulation; 2) 3,5-dihydroxyphenylglycine (DHPG, 30 mu M)-induced depression of synaptic transmission; and 3) learning of the hidden platform version of the water maze by mice. BAY 36-7620 (10 mu M) amplified LTP but, like the mGIuR1 antagonists 7-hydroxyiminocyclopropan[b]chromen-1a-carboxylic acid ethyl ester (CPCCOEt, 10 mu M) and 4-carboxyphenylglycine (4-CPG, 50 mu M), diminished LTP at 1 mu M. The mGluR5 antagonist 6-methyl-2-(phenylethynyl)-pyridine (MPEP, 10 mu M) had no effect. BAY 36-7620 (10 mu M) did not affect strong LTP. Thus, mGlu 1, but not mGlu 5, receptors modulate UP elicited by weak stimulation in vitro. DHPG-induced depression of synaptic transmission was only marginally affected by BAY 36-7620 (1 mu M) or 4-CPG (100 mu M). In a mouse water maze study, BAY 36-7620 (10 mg/kg, i.v.) increased the escape latency and impaired water escape task acquisition during the first 4 days. Drug- and vehicle-treated groups showed comparable performance at day 5. Our data support a role for mGluR1 in UP and in the acquisition of spatial memory. (C) 2008 IBRO. Published by Elsevier Ltd. All rights reserved.