Behavioral effects associated with chronic ketamine or remacemide exposure in rats

Abstract

The effects of chronic exposure to ketamine or remacemide on the acquisition and performance of food-reinforced operant behaviors was assessed in female Sprague-Dawley rats. Ketamine is an anesthetic N-methyl-D-aspartate (NMDA) receptor antagonist, whereas remacemide is an active central nervous system compound with both NMDA receptor antagonist and sodium channel blocking properties. Learning, audio/visual discrimination and motivation were modeled using incremental repeated acquisition (IRA), audio/visual discrimination (AVD) and progressive ratio (PR) tasks, respectively. Ketamine (10 or 100 mg/kg/day), remacemide (100 or 150 mg/kg/day) or water was administered daily (7 days/week) via orogastric gavage beginning on postnatal day (PND) 23 and continuing until PND 257. Monday through Friday behavioral assessments began on PND 27 and continued until PND 383. Chronic treatment with the high dose of ketamine decreased response rate in all tasks suggesting decreased motivation or motoric capabilities. Chronic treatment with ketamine or remacemide had no effect on the acquisition of IRA task performance at any dose tested. While chronic treatment with either high-dose ketamine or low-dose remacemide only delayed the acquisition of AVD task performance for a brief period midway through treatment, chronic treatment with high-dose remacemide delayed the acquisition of AVD task performance until late in treatment. The findings for ketamine are quite different from those of MK-801 (the prototypic NMDA receptor antagonist) in a previous rat study in which MK-801 severely disrupted the acquisition of both IRA and AVD task performances. These observations suggest important differences in the mechanism of action between ketamine and MK-801. For example, ketamine has a much lower binding affinity than MK-801 for the NMDA receptor, the dopamine transporter and the dopamine D2 receptor. In addition, the findings for remacemide observed in rats are in marked contrast with those seen in monkeys where chronic remacemide had profound disruptive effects on the acquisition of both IRA and AVD task performances and suggest important species differences.