NOVELTY-INDUCED ACTIVITY-REGULATED CYTOSKELETAL-ASSOCIATED PROTEIN (ARC) EXPRESSION IN FRONTAL CORTEX REQUIRES SEROTONIN 2A RECEPTOR ACTIVATION

Many psychiatric disorders are characterized by cognitive and emotional alterations that are related to abnormal function of the frontal cortex (FC). FC is involved in working memory and decision making and is activated following exposure to a novel environment. The serotonin 2A receptor (5-HT2AR) is highly expressed in the FC where its activation induces hallucinations, while blockade of 5-HT(2A)Rs contributes to the therapeutic effects of atypical antipsychotic drugs. The purpose of the present study was to investigate the involvement of 5-HT2AR in FC activation following exposure to a novel environment. As an output of FC activation we measured expression of activity-regulated cytoskeletal-associated protein (Arc). Novelty-exposure (open-field arena) robustly up-regulated FC Arc mRNA expression (similar to 160%) in mice compared to home-cage controls. This response was inhibited with the 5-HT2AR antagonists ketanserin and MDL100907, but not with the selective 5-HT2cR antagonist SB242084. Novelty-exposure also induced Arc mRNA expression in hippocampus (similar to 150%), but not in cerebellum or brainstem. Pretreatment with 5-HT2AR antagonist ketanserin did not repress the Arc induction in hippocampus, indicating that the involvement of 5-HT2AR in this response is restricted to the FC. Similarly, the novelty-induced stress as determined by increasing levels of plasma corticosterone, was not influenced by 5-HT2AR antagonism suggesting that Arc mRNA and stress are activated via distinct mechanisms. Taken together, our results demonstrate that the induction of Arc in the FC following exposure to a novel environment is dependent on the 5-HT2AR, and that the simultaneous release of corticosterone is regulated via another system independent of 5-HT2AR activation. (C) 2011 IBRO. Published by Elsevier Ltd. All rights reserved.