Pro-inflammatory cytokines are known to be elevated in several neuropathological states. We have previously demonstrated in our laboratories that tumour necrosis factor (TNF)-α inhibits long-term potentiation (LTP) in the dentate gyrus region of the rat hippocampus. This inhibition is biphasic consisting of an early phase that is dependent on activation of the p38 mitogen activated protein kinase (MAPK) and a later phase, possibly dependent on protein synthesis (Butler et al., 2002, 2004). Many of the factors involved in the early modulation of LTP by TNF-α have yet to be elucidated, including the role of metabotropic glutamate receptors (mGluRs). We have therefore investigated the effect of two (mGluR) antagonists on the TNF-α mediated depression of LTP in the rat dentate gyrus in vitro. Recordings of field excitatory postsynaptic potentials (EPSPs) were made from the medial perforant path using standard in vitro methods; rats were humanely killed. Data are expressed as mean±sem and analysed using Students unpaired t-test. Application of TNF-α (5.5ng/ml; 465pM) to the hippocampal slice 20 min prior to high frequency stimulation (HFS; 8 trains of 8 pulses at 2 s intervals), resulted in a significant impairment of early (1 hr) and late (3 h) LTP in the presence of TNF-α. At 1 and 3 hr post HFS EPSP slope was 126.8±7.6%, and 82.7±8.0%, verus control LTP of 180.0±3.0% and 158.3±3.3%, respectively, P< 0.001; n=7 for both time-points). Perfusion of the non-specific mGluR antagonist MCPG (500μM) or the specific mGluR1 antagonist AIDA (435μM) caused a small but non-significant reduction in LTP at 1 hr. However at 2 hr AIDA significantly reduced LTP (141.2±11.1% versus control LTP of 169.9±3.9% at 2 hr; P<0.05; n=5). Perfusion of MCPG or AIDA for 40 min prior to application of TNF-α significantly reversed the inhibitory effect of TNF-α on LTP (132.0±13.0% and 128.8±6.6% at 2 hr, respectively, compared to TNF-α alone, n=4-5). These results show a novel role for mGluRs in the TNF-α inhibition of LTP. A connection between the activation of mGluRs and the p38 MAPK remains to be resolved. These studies will provide valuable tools to forward our understanding of the mechanisms of action of TNF-α on synaptic plasticity.