Novelty enhances retrieval: molecular mechanisms involved in rat hippocampus

Rats exposed to a novel environment just prior to or 1-2 h, but not 4 or 6 h, before retention testing exhibited an enhanced retrieval of a one-trial inhibitory avoidance training. The bilateral intrahippocampal infusion of P D098059, an inhibitor of mitogen-activated protein kinase (MAPK), the speci fic upstream activator of p42 and p44 MAPKs, given 10 min before the exposu re to the novel environment, blocked the enhancing effect of novelty on mem ory retrieval. In addition, prenovelty infusion of DL-2-amino-5-phosphonova lerate (APV), an antagonist of glutamate NMDA receptors, produced similar e ffects. The exposure to the novel environment is associated with an activat ion of p42 and p44 MAPKs and an increase in the phosphorylation state of th e transcription factor cAMP response element binding protein (CREB). No cha nges were observed in cAMP-dependent protein kinase (PKA) activity or in al pha -CAMKII activation. Taken together, our results indicate that novelty a ctivates hippocampal MAPKs, which are necessary, along with glutamate NMDA receptors, for the enhancing effect of novelty on retrieval.