Evaluation of the effect of chronic administration of drugs on rat behavior in the water maze task.

Tissue accumulation of intermediates of the metabolism occurs in various inherited neurodegenerative disorders, including methylmalonic acidemia (MA). Animal cognition is usually tested by measuring learning/memory of rats in behavioral tasks. A procedure in which rats are chronically injected with the metabolites accumulating in the neurometabolic disorder methylmalonic acidemia from the 5th to the 28th day of life is described. The animals were allowed to recover for approximately 30 days, after which they were submitted to the Morris water maze task. This behavioral task consisted of two steps. The first one is called the acquisition phase, where rats were trained for 5 consecutive days performing four trials per day to find the submerged platform. On each trial, the rat was placed in the water in one of four start locations (N, S, W and E). The animal was then allowed to search for the platform for 60 s. Once the rat located the platform, it was permitted to remain on it for 10 s. The acquisition phase was followed by the probe trial 24 h later, in which the platform is not present. The time spent in the quadrant of the former platform position and the correct annulus crossings were obtained as a measure for spatial memory. The next step was the reversal learning (reversal phase) performed 2 weeks later. Animals were trained for 4 days (four trials per day) to find the hidden platform, which had now been moved to a position diagonally opposite (reversed) from its location in the acquisition phase. On the next day, all animals were submitted to a second probe trial, similar to the first one. We observed that rats chronically injected with methylmalonic acid (MA), although presenting no alterations in the acquisition phase, showed a long lasting reversal learning impairment. Moreover, motor activity, evaluated by the swim speed in the maze, was not altered by MA administration. These results are consistent with perseverative behavior.