The immune system is an important modulator of learning, memory and neural plasticity. Interleukin 1β (IL-1β), a pro-inflammatory cytokine, significantly affects several cognitive processes. Previous studies of our group have demonstrated that the intrahippocampal administration of IL-1β impairs reconsolidation of contextual fear memory. This effect was reversed by the melanocortin alpha-melanocyte-stimulating hormone (a-MSH). The mechanisms underlying the effect of IL-1β on memory reconsolidation have not been established yet. Our results demonstrate that IL-1β produced a significant decrease in the glutamate release from dorsal hippocampus synaptosomes after reactivation of the fear memory. Examination of the cytosolic Ca2+ using Fluo-3AM revealed that the inhibition of glutamate release could be attributed to a reduction in voltage-dependent Ca2+ influx. Also, western blot analysis demonstrated that IL-1b reduced the phosphorylation of GluR1 AMPA subunit. The intrahippocampal administration of α-MSH can modulate these effects. Our results establish a possible mechanism involved in the detrimental effect of IL-1β on memory reconsolidation and also that α-MSH may exert a beneficial modulatory role in preventing IL-1β effects.