Chronic difluoromethylornithine treatment impairs spatial learning and memory in rats.
Recent evidence suggests that polyamines putrescine, spermidine and spermine are essential in maintaining normal cellular function. The present study investigated the effects of chronic treatment of difluoromethylornithine (DFMO, 3% in drinking water), a potent inhibitor of putrescine synthesis, for 54 consecutive days on animals'behavior and neurochemical levels in the CA1, CA2/3 and dentate gyrus sub-regions of the hippocampus and the prefrontal cortex. The DFMO group showed performance impairments in the place navigation and the probe test conducted 24 h after the training in the reference memory version of the water maze task, but not in the elevated plus maze, open field, object recognition, cued navigation and the working memory version of the water maze task when compared to the control group (drinking water only). DFMO treatment resulted in approximately 80-90% and 20% of reductions in the putrescine and spermidine levels, respectively, in the four brain regions examined, and a small reduction in agmatine level in the CA2/3, with no effects on spermine, glutamate and γ-aminobutyrate. The DFMO group showed decreased body weight relative to the control one. However, there were no significant differences between groups in the normalized brain, kidney and liver weights. The present study demonstrates that chronic treatment of DFMO depletes putrescine and decreases spermidine levels in the brain, inhibits growth, and impairs spatial learning and memory in the reference memory version of the water maze specifically. These findings merit further investigation to fully understand the functional role of endogenous polyamines in learning and memory.
Department of Anatomy, University of Otago, Dunedin, New Zealand.
Neeraj
N
Gupta
Hu
H
Zhang
Ping
P
Liu
D000376:Agmatine / Q000378:metabolism; D000818:Animals; D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000009:adverse effects; D001522:Behavior, Animal / Q000187:drug effects; D000518:Eflornithine / Q000008:administration & dosage / Q000009:adverse effects*; D004791:Enzyme Inhibitors / Q000008:administration & dosage / Q000009:adverse effects*; D006624:Hippocampus / Q000187:drug effects* / Q000378:metabolism; D007859:Learning Disabilities / Q000139:chemically induced*; D008297:Male; D018782:Maze Learning; D008568:Memory / Q000187:drug effects; D008569:Memory Disorders / Q000139:chemically induced*; D009928:Organ Specificity; D065108:Ornithine Decarboxylase Inhibitors; D017397:Prefrontal Cortex / Q000187:drug effects* / Q000378:metabolism; D011700:Putrescine / Q000378:metabolism; D011897:Random Allocation; D051381:Rats; D017207:Rats, Sprague-Dawley; D013037:Spatial Behavior / Q000187:drug effects; D013095:Spermidine / Q000378:metabolism; D036401:Toxicity Tests, Chronic
D000970:Antineoplastic Agents; D004791:Enzyme Inhibitors; D065108:Ornithine Decarboxylase Inhibitors; D000376:Agmatine; D013095:Spermidine; D011700:Putrescine; D000518:Eflornithine