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Blocking OX1R impairs spatial learning in MWM in a training-dependent manner.Strong vs weak training in a spatial task increases HPC-thalamic-cortical activity.SB-334867 diminishes c-Fos expression in areas with a high density of OX1R.Training compensates for SB-334867 impairing effects on MWM and c-Fos expression.Activation of DG, gRSC, PL and CL could prevent impairment of MWM by SB-334867.It has been suggested that the orexin system modulates learning and memory-related processes. However, the possible influence that training could have on the effect of the blockade of orexin-A selective receptor (OX1R) on a spatial memory task has not been explored. Therefore, the present study attempts to compare the effects of OX1R antagonist SB-334867 infusion on spatial memory in two different conditions in the Morris Water Maze (MWM). This experiment evaluated the animals’ performance in weak training (2 trials per session) vs strong training (6 trials per session) protocols in a spatial version of the MWM. We found that in the 2-trial condition the post-training SB-334867 infusion had a negative effect on consolidation as well as on the retention and reversal learning of the task 72h later. This effect was not apparent in the 6-trial condition. In addition, while the strong training groups showed a general increase in c-Fos expression in several brain areas of the hippocampal-thalamic-cortical circuit, SB-334867 administration had the opposite effect in areas that have been previously reported to have a high density of OX1R. Specifically, the SB-infused group in the 2-trial condition showed a decrease in c-Fos immunoreactivity in the dentate gyrus, granular retrosplenial and prelimbic cortices, and centrolateral thalamic nucleus. This was not observed for subjects in the 6-trial condition. The activation of these areas could constitute a neuroanatomical substrate involved in the compensatory mechanisms of training upon SB-334867 impairing effects on a MWM spatial task.