|Budget Amount *help
¥2,200,000 (Direct Cost: ¥2,200,000)
Fiscal Year 1990: ¥500,000 (Direct Cost: ¥500,000)
Fiscal Year 1989: ¥1,700,000 (Direct Cost: ¥1,700,000)
1) For evaluating the therapeutic potential of nootropic drugs, it is most desirable to establish relevant methods for measuring "learning and memory" in animals. The Delayed Matching-to-Sample Procedure (DMSP) is one of the experimental methods for determining short-term memory. I established two new methods for the study of working memory in the rat, using the DMSP in 3-lever operant apparatus and 3- panel runway apparatus.
In the 3-panel runway task, scopolamine (0.56mg/kg i. p.) and AF 64A (2.5nmol bilaterally injected into the dorsal hippocampus) significantly increased errors (the number of times an animal pushed an incorrect panel-gate) and latency (the time required for the animal to take food-pellets on the plate of the goal box). In the 3-lever operant task, scopolamine (0.32mg/kg i. p.) decreased the number of reinforces in test trials without decreasing that in training trials. These findings suggest that dysfunction of cholinergic system lead to disturbances of the working
memory (short-term memory) in both tasks.
On the other hand, olfactory bulbectomy and dorsal hippocampus lesions impaired the working memory in both tasks, but lesions of the mammillary body did not in the operant task.
The impairment of working memory produced by scopolamine or ischemia in a 3-panel runway task was ameliorated by cholinesterase inhibitors Tetra-Hydro-Aminoacridine (THA) and amiridin, cholinergic activators WEB 1881 FU and minaprine, and a methyl donor S-adenosyl-L-methionine.
2) In order to clarify the discriminative stimulus properties of THA and amiridin. Two different groups of rats were trained to discriminate either amiridin (10mg/kg i. p.) or THA (1.8mg/kg i. p.) from saline on a standard two-lever Food-Reinforced procedure (FR10). Cholinesterase inhibitors amiridin. THA and physostigmine produced a dose-dependent drug-appropriate responding both in amiridin and in THA trained rats. Arecoline substituted completely for amiridin stimuli and partially for THA stimuli. Both the amiridin and THA stimuli were blocked by scopolamine. On the other hand, lisuride alsoproduced full drug-appropriate responding in both trained rats, and amantadine produced full and 60% drug-appropriate responding in the amiridin and THA trained rats, respectively.
However, haloperidol, SCH 23390 and sulpiride failed to antagonize both discriminative stimuli. Further, non-competitive NMDA antagonists phencyclidine and dextrophan, and nootropic drugs WEB 1881 FU and calcium hopantenate showed partial generalization to the amiridin and THA stimuli. These results indicate that cholinergic facilitation is important for the discriminative stimuli of amiridin and THA. Less