THE EFFECTS OF MEMANTINE ON THE BEHAVIOR OF AGED RATS IN THE MORRIS WATER MAZE.
ARL NSMA, University of Arizona, Tucson, AZ
Memantine is a noncompetitive antagonist of the NMDA receptor, which has been approved by the FDA for the treatment of cognitive impairments associated with Alzheimer’s disease. It is also being tested for the treatment of other neurological diseases that may be mediated by the NMDA receptor. Because of its unusual kinetics of binding to the NMDA receptor, it is thought not only to alleviate the effects of over stimulation of the NMDA receptor without significant side effects, but may actually improve learning mediated by the NMDA receptor in some circumstances. In adult rats, memantine has been shown to increase the maintenance of long-term potentiation (LTP) in the hippocampus and the retention of the location of the hidden platform in the spatial version of the Morris water maze swim task (Barnes et al., 1996). In aged rats, which show selective changes in LTP maintenance and induction of long-term depression (LTD), memantine has been shown to alleviate impairments in experience-dependent place field expansion plasticity (Burke et al., 2005). This form of plasticity is dependent on the NMDA receptor (Ekstrom et al., 2001). Interestingly, a relationship between the amount of place field expansion plasticity and watermaze performance in aged rats has also been observed. Therefore, the current investigation was designed to see if memantine could improve learning on the Morris water maze in aged, learning impaired rats. Aged rats were tested on spatial and cued versions of the Morris water maze task as described previously (Barnes et al., 1997), and injected with 10mg/kg of memantine or saline 20 minutes prior to the first trial of water maze testing each day for five consecutive days. The rats injected with saline showed some improvement in finding the hidden platform, and showed good cue learning. The aged rats injected with memantine, however, performed worse on both tasks. The behavior of the memantine rats was very different from the saline controls, however. They voluntarily jumped into the water after being placed on the platform, and often swam around the visible platform without climbing onto it. Several explainations for this observation can be offered, one of which is the hypothesis that the anxiolytic and analgesic effects of memantine could make swimming in the cold water less aversive. There is some support for the use of memantine in the treatment of depression and anxiety; the present data may support this use.
Supported by: AG012609, AG010546