Pro‐cognitive action of CART is mediated via ERK in the hippocampus

Abstract

Although cocaine‐ and amphetamine‐regulated transcript peptide (CART) is detected in several cortical and subcortical areas, its role in higher functions has been largely ignored. We examined the significance of CART in memory formation and tested if the downstream actions of CART involve N‐methyl‐d‐aspartate (NMDA) activated extra‐cellular signal‐regulated kinase (ERK). Newly formed memory was evaluated using novel object recognition test consisting of familiarization (T1) and choice trials (T2). The choice trials were performed at two time points: 30‐min (T230‐min) and 24‐h (T224‐h) postacquisition. In choice trial (T230‐min), vehicle control rats explored the novel object for significantly longer duration than the familiar object indicating intact memory formation. However, CART‐antibody, U0126 [ERK antagonist, both via intracerebroventricular (icv) or intrahippocampal (ih) route] or MK‐801 (NMDA antagonist; intraperitoneal) treated rats spent less time exploring novel objects; CART peptide (icv or ih) was ineffective. During choice trial at T224‐h, a significant decrease in novel object exploration time was noticed in vehicle control rats suggesting amnesia. However, treatment with CART, prior to familiarization trial (T1), promoted exploration of the novel object even at T224‐h. Pretreatment with U0126 or MK‐801 blocked pro‐cognitive‐like effect of CART suggesting involvement of NMDA‐ERK pathway in CART's action. Animals subjected to the object familiarization trial showed a drastic increase in the CART‐immunoreactivity in the cells of cornu ammonis 3 and polymorph layer of dentate gyrus, and fibers within ento‐ (ENT) and peri‐rhinal (PRH) cortices. Western blot analysis revealed that CART treatment significantly up‐regulated the expression of phospo‐ERK1/2 in hippocampus, ENT and PRH. This effect was attenuated following pretreatment with U0126 or MK‐801, suggesting the activation of ERK signaling cascade through NMDA receptors. Thus, CART system seems to play an important role in recognition memory and that these effects may be mediated by NMDA receptors‐ERK signaling in the ENT/PRH‐hippocampal circuit.