| Summary: | Rats were injected daily with two doses of HCY (20-mg/kg and 200-mg/kg) for variable duration and spatial memory was assessed in the water maze. Animals were tested 30min after injection using two paradigms: 1) the reference memory (RM) paradigm in which the position of the platform in the water maze was kept constant over days in order to test long-term memory, 2) the delayed matching to position (DMTP) paradigm in which the platform position changed every day in order to test working/short-term memory. We found that HCY induced a differential effect on memory depending on animal’s age and the task employed. In the first group of animals, HCY administration for 13 weeks, in contrast to all expectations, enhanced reversal learning in reference memory paradigm in 8-10 weeks old animals, with no effect on the acquisition or memory retention in the probe trials. In the second group of animals, in contrast to young animals, HCY administration enhanced memory of young-adult rats (5-month old) when a DMTP task was employed. At the level of receptors, HCY enhancement is unlikely to be mediated via NMDA receptors alone, because HCY failed to revert MK801-induced (NMDA receptors antagonist) memory impairment observed with a DMTP task. Surprisingly, we found that HCY partially reversed scopolamine-induced memory impairment, which may indicate that HCY has some activity on cholinergic system. In the third group of animals (1-year-old), HCY administration for 2 weeks, in contrast to the 5-month old rats, impaired memory in the DMTP task. Also, we found that HCY plasma level in the 200-mg/kg group was about 600% more than controls. This may reflect a reduced ability to clear HCY which may explain the absence of any impairment in young animals where HCY level increased by 50% only after 13 weeks of treatment. In conclusion, given that memory impairment was observed in old animals may indicate that hyperhomocysteinemia probably plays a role in AD. However, HCY effects are overt only in already predisposed old patients.
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