Evaluation of changes in hippocampal gene expression associated with aging and the behavioral effects of chronic exposure to ketamine or remacemide

N-methyl-D-aspartate (NMDA) receptors are vital for central nervous system development and function. They mediate long-term potentiation, which is linked to learning and memory processes, and participate in the regulation of neuronal survival and synaptic plasticity. Therefore, the disruption of NMDA receptor activity (i.e., NMDA receptor hypofunction) at critical developmental time points or for prolonged periods could theoretically lead to neuronal injury (i.e., permanent alterations in neuronal structure and, presumably, function). Since sodium channels play a crucial role in the early phases of neuronal injury, the concurrent inhibition of sodium channel activity could theoretically attenuate the adverse effects associated with NMDA receptor hypofunction.;In order to explore the relative contributions of NMDA receptor and sodium channel blockade on the acquisition and performance of several complex operant behaviors, ketamine or remacemide was administered chronically to Sprague-Dawley rats. Ketamine is a noncompetitive NMDA receptor antagonist, whereas remacemide is a noncompetitive NMDA receptor antagonist with significant sodium channel blocking activity. The adverse behavioral effects associated with chronic ketamine or remacemide exposure were selective for the acquisition of the auditory/visual discrimination and motivation tasks rather than the acquisition of the learning task. The effects of chronic ketamine exposure were quite different from those of MK-801 (the prototypic NMDA receptor antagonist) in a previous rodent study and suggest important differences in the mechanism of action between ketamine and MK-801.;In order to begin characterizing the molecular mechanisms that might be associated with chronic ketamine or remacemide exposure, changes in hippocampal gene expression were assessed at six different time points after the start of drug administration. Chronic exposure to either ketamine or remacemide significantly decreased the expression of genes involved in feeding behavior, immune responses, Notch signaling, protein ubiquitination, stress responses and vitamin biosynthesis. In addition, chronic remacemide exposure significantly decreased the expression of genes involved in amyloid processing, apoptosis, calcium signaling, ERK signaling and oxidative stress and significantly increased the expression of genes involved in DNA repair and nucleotide excision repair. These findings suggest important differences in the cellular responses to chronic ketamine or remacemide exposure.