Over the past several decades, neurobiological research on memory has been focused on the mechanisms underlying memory storage. Nevertheless, the study of forgetting and, specifically, active and selective forgetting has been increased since Anderson et al. showed in 1994 that the retrieval of certain memories could cause the forgetting of related, but not explicitly evoked information by a mechanism called retrieval-induced forgetting (RIF). Humans and rats share the fundamental features of RIF: competition-dependent, cue-independent, and reliant on the prefrontal cortex. This work aims to explore if and how the serotonergic system participates in RIF. Precisely, we first used an antagonist of the serotonin receptor 2A (5-HT2AR), then specific inhibitors for members of the βarr2 signaling pathway, and finally an agonist of the 5-HT2AR in the medial prefrontal cortex. We found that a 5-HT2AR antagonist and a PI3K inhibitor, which is part of the Barr2 pathway impaired RIF but did not affect memory in other ways. Moreover, injection of a 5-HT2AR agonist promoted RIF in animals that would not normally forget. In summary, 5-HT2AR signaling in the rat prefrontal cortex is necessary for the occurrence of RIF and is partially reliant on the activation of the Barr2 pathway.