The dorsolateral periaqueductal grey N-methyl-D-aspartate/nitric oxide/cyclic guanosine monophosphate pathway modulates the expression of contextual fear conditioning in rats

Abstract

The dorsolateral periaqueductal grey (dlPAG) plays an essential role in unconditioned fear responses and could also be involved in the expression of contextual fear responses. Activation of glutamate N-methyl-D-aspartate (NMDA) receptors and the nitric oxide (NO) pathway in this region facilitates anxiety-like responses. In the present study we investigated if antagonism of NMDA receptors or inhibition of the NO pathway in the dlPAG would attenuate behavioral and cardiovascular responses of rats submitted to a contextual fear-conditioning paradigm. Male Wistar rats with unilateral cannulae aimed at the dlPAG were re-exposed to a chamber where they had received footshocks 48 h before. Ten min before the test the animals received an intra-dlPAG injection of vehicle, AP7 (NMDA receptor antagonist), N-propyl-L-arginine (neuronal NO synthase inhibitor), carboxy-PTIO (NO scavenger) or 1H-[1,2,4] oxadiazolol [4,3-a]quinoxalin-1-one (ODQ) (guanylate cyclase inhibitor). Freezing and cardiovascular responses were recorded continuously for 10 min. Intra-dlPAG administration of AP7 before re-exposure to the aversively conditioned context attenuated these responses. Similar effects were observed after the NO synthase inhibitor, NO scavenger or guanylate cyclase inhibitor. Our findings suggest that activity of dlPAG NMDA/NO/cyclic guanosine monophosphate (cGMP) pathway facilitates the expression of contextual fear responses.