METRIFONATE IMPROVES SPATIAL NAVIGATION AND AVOIDANCE-BEHAVIOR IN SCOPOLAMINE-TREATED, MEDIAL SEPTUM-LESIONED AND AGED RATS

We investigated the effects of acute p.o. pretraining treatment with a n indirect acetylcholinesterase inhibitor, metrifonate, on water maze spatial navigation and passive avoidance behavior. Metrifonate (10-100 mg/kg, orally, p.o.) did not improve the water maze or passive avoida nce performance of young intact rats. However, in young rats metrifona te over a broad dosage range (10-100 mg/kg, p.o.) was able to alleviat e the adverse effects of scopolamine (a muscarinic acetylcholine recep tor antagonist; 0.4 and 2.0 mg/kg in water maze and passive avoidance study, respectively) and medial septum-lesioning on spatial reference and working memory and passive avoidance performance. In old (23-month -old) rats, a defect of water maze and passive avoidance behavior was observed. In old rats, metrifonate improved spatial reference memory f unction in the water maze and also passive avoidance at 10-30 mg/kg, b ut the 3 mg/kg dose was ineffective. Very old (27-month-old) rats had a more severe impairment of water maze performance than old rats, and metrifonate 3-30 mg/kg did not improve their spatial navigation. These results show that metrifonate may over a wide range of doses stimulat e cognitive functioning, but during advanced aging neurobiological def ects develop that may mask some of the therapeutic effects of metrifon ate in rats.