Consistent with the importance of the hippocampus in learning more complex stimulus relations, but not in simple associative learning, the dorsal hippocampus has commonly been implicated in classical fear conditioning to context, but not to discrete stimuli, such as a tone. In particular, a specific and central role in contextual fear conditioning has been attributed to mechanisms mediated by dorsal hippocampal N-methyl-D-aspartate (NMDA)-type glutamate receptors. The present study characterized the effects of blockade or tonic stimulation of dorsal hippocampal NMDA receptors by bilateral local infusion of the noncompetitive NMDA receptor antagonist MK-801 (dizocilpine maleate; 6.25mug/side) or of NMDA (0.7mug/side), respectively, on classical fear conditioning to tone and context in Wistar rats. Freezing was used to measure conditioned fear. Regardless of whether conditioning was conducted with tone-shock pairings or unsignaled footshocks (background or foreground contextual conditioning), both NMDA and MK-801 infusion before conditioning resulted in reduced freezing during subsequent exposure to the conditioning context. Freezing during subsequent tone presentation in a new context, normally resulting from conditioning with tone-shock pairings, was not impaired by MK-801 but was strongly reduced by NMDA infusion before conditioning; this freezing was also reduced by NMDA infusion before tone presentation (in an experiment involving NMDA infusions before conditioning and subsequent tone presentation to assess the role of state-dependent learning). It was assessed whether unspecific infusion effects (altered sensorimotor functions, state dependency) or infusion-induced dorsal hippocampal damage contributed to the observed reductions in conditioned freezing. Our data suggest that formation of fear conditioning to context, but not tone, requires NMDA receptor-mediated mechanisms in the dorsal hippocampus. As indicated by the effects of NMDA, some dorsal hippocampal processes may also contribute to fear conditioning to tone. The role of the dorsal hippocampus and local NMDA receptor-mediated processes in fear conditioning to tone and context is discussed in comparison with ventral hippocampal processes. (C) 2003 Wiley-Liss, Inc.
