Neuropharmacology 41 (2001) 1–7 www.elsevier.com/locate/neuropharm The metabotropic glutamate receptor antagonist 2-methyl-6- (phenylethynyl)-pyridine (MPEP) blocks fear conditioning in rats Brigitte Schulz a , Markus Fendt a , Fabrizio Gasparini b , Kurt Lingenho ¨hl b , Rainer Kuhn b , Michael Koch c,* a Animal Physiology, University of Tu ¨bingen, Tu ¨bingen, Germany b Novartis Pharma AG, Basle, Switzerland c Brain Research Institute, University of Bremen, PO Box 33 04 40, 28334 Bremen, Germany Received 7 November 2000; received in revised form 12 February 2001; accepted 12 March 2001 Abstract Glutamate receptors play an essential role in fear-related learning and memory. The present study was designed to assess the role of the group I metabotropic glutamate receptor (mGluR) subtype 5 in the acquisition and retrieval of conditioned fear in rats. The selective mGluR5 antagonist 2-methyl-6-(phenylethynyl)-pyridine (MPEP) was applied systemically (0.0, 0.3, 3.0, 30.0 mg/kg per os) 60 min before the acquisition training and before the expression of conditioned fear, respectively, in the fear-potentiated startle paradigm. MPEP dose-dependently blocked the acquisition of fear. This effect was not due to state-dependent learning. MPEP also prevented the expression of fear at a dose of 30.0 mg/kg. As a positive control for these effects, we showed that the benzodiazepine anxiolytic compound diazepam (1.25 mg/kg intraperitoneally) also blocked acquisition and expression of fear potentiated startle. MPEP did not affect the baseline startle magnitude, short-term habituation of startle, sensitisation of startle by footshocks or prepulse inhibition of startle. These data indicate a crucial role for mGluR5 in the regulation of fear conditioning. In the highest dose MPEP might exert anxiolytic properties.  2001 Elsevier Science Ltd. All rights reserved. Keywords: Acoustic startle response; Fear; Learning; Memory; Metabotropic glutamate receptors; Prepulse inhibition 1. Introduction Fear conditioning is a simple form of Pavlovian con- ditioning that serves as a model for learning and memory (Fendt and Fanselow, 1999; LeDoux, 1992). The mech- anisms underlying the acquisition and retrieval of con- ditioned fear in rodents are also relevant for the under- standing of human fear and anxiety, and possibly for the design of new anxiolytic compounds (Davis et al., 1993). In Pavlovian fear conditioning paradigms, a neutral stimulus is paired with an aversive event and comes to predict this aversive event even after very few pairings. After training the conditioned stimulus elicits or potentiates protective responses such as the acoustic * Corresponding author. Tel.: +49-421-2187278; fax: +49-421- 2184932. E-mail address: michael.koch@uni-bremen.de (M. Koch). 0028-3908/01/$ - see front matter  2001 Elsevier Science Ltd. All rights reserved. PII:S0028-3908(01)00036-3 startle response (ASR), freezing, vocalisation or an increase in arterial blood pressure (LeDoux, 1995). Glutamate receptors play an essential role in learning and memory and, therefore, are also involved in fear conditioning. Both types of ionotropic glutamate recep- tors contribute to conditioned fear. For example, it has been shown that the acquisition of fear in the fear- potentiated startle paradigm can be blocked by intra- amygdaloid infusion of the NMDA receptor antagonist AP-5 (Miserendino et al., 1990; Gewirtz and Davis, 1997). The retrieval of fear memories in this paradigm was blocked by intra-amygdaloid infusion of the AMPA/Kainate receptor antagonist CNQX (Kim et al., 1993). The contribution of mGluRs to fear conditioning is less well investigated although it is known that mGluRs are involved in learning (Riedel, 1996). Group I mGluR antagonists blocked memory consolidation of contextual conditioning (Nielsen et al., 1997) and fear- conditioning led to a transient up-regulation of mGluR5 in the hippocampus (Riedel et al., 2000). A previous