The anterior cingulate ERK pathway contributes to regulation of behavioral excitement and hedonic activity.

Several intracellular signaling cascades, such as the extracellular signal-regulated kinase (ERK), Wnt-signaling/GSK-3, PLC/PKC, and PI3K pathways, have been shown to be affected directly or indirectly by mood stabilizers. Clinical imaging studies reveal that mood disorders are associated with structural and/or metabolic changes in specific brain regions such as the anterior cingulate cortex (ACC). Here we investigated the extent to which perturbation of one of the affected pathways, the ERK pathway, in the ACC influences affective-related behavior. The regional perturbation was induced by two means: local continuous infusion of PD98059, an ERK pathway inhibitor, and microinjection of a lentiviral-mediated gene delivery system encoding functional negative ERK1. The outcomes were monitored with a battery of affective-related tests similar to those used in several previous studies. Compared to their respective controls, rats infused with PD98059 or injected with the lentiviral negative ERK1 construct displayed hyperactivities in multiple tests, exhibited preferentially more open-arm activity in the elevated-plus-maze test, consumed more sweetened liquid in a saccharin preference test, and showed heightened response to amphetamine. These data support a role for the ACC ERK pathway in the regulation of affective-related behaviors. However, the medial prefrontal cortex (mPFC) comprises at least three other regions that will need to be similarly examined before specific roles of the ACC ERK pathway can be definitively attributed to affective behaviors. Additionally, responses of other signaling pathways to mood stabilizers in these mPFC regions, as well as the limbic regions to which they project, will be important to examine.