NAKAMURA Shigenobu Hiroshima Univ. School of Medicine, professor, 医学部, 教授 (30026843)
KITO Syozo Univ. of the Air Fuculty of Liberal Acts, professor, 教養学部, 教授 (00010140)
三好 理絵 広島大学, 医学部, 助手 (80209965)
郡山 達男 広島大学, 医学部附属病院, 助手 (80195693)
|Budget Amount *help
¥2,000,000 (Direct Cost: ¥2,000,000)
Fiscal Year 1990: ¥1,000,000 (Direct Cost: ¥1,000,000)
Fiscal Year 1989: ¥1,000,000 (Direct Cost: ¥1,000,000)
Acetylocholine (ACh) has been considered to be involved in the higher brain function such as learning and memory in the cerebral cortex and hippocampus, while in the basal ganglia and cerebellum it has relations with movement. It is important to elucidate the turnover of ACh in the brain not only inthe basic neuroscience but also for understanding of pathophysilogy and treatment of neurodegenerative disorders such as Alzheimer's disease. In this research project, we established the method for measuring ACh contents from in vivo dialysis samples of the brain. By use of method, the effects of various neurotransmitters and drugs on the release of ACh were studied in the rat brain.
First, we estabilished the method for measuring the endogenous ACh release in the striatum and hippocampus. The dialysis probe which was equipped with a semipermeable tube, was inserted into the rat brain. On perfusion experiments, rats were allowed to move freely and perfused with a Ringer solution. The perfusat
es were collected with 20-min intervals and, ACh contents were measured by HPLC. When perfused with a Ringer solution, ACh contents were very low and not detectable. On the other hand, they were able to be detected in the presence of an anticholinesterase, physostigmine. Thus, we confirmed that ACh in the perfusates was released from cholinergic nerve terminals. As the next step, effects of neuropeptides, cholinergic drugs and nerve growth factor on ACh release were studied. Peripheraly administration of cholecystokinin induced an increase of ACh release in the striatum, and the results suggested that the action of the peptide was, in part, mediated via vagal afferent impulses. Neurotensin did not affect the striatal cholinergic release, while it increased the release of dopamine and its metabolites. A muscarinic ACh receptor agonist inhibited the release of ACh in the striatum, whereas an antagonist stimulated it. In addition, LH-RH had no effect on the hippocampal ACh release, while it decreased the release of glutamate.
In summary, the mechanisms of ACh release and its modulation by other neuroactive substances were investigated in the rat brain. Since the experimental system is in vivo, these results have possibilities for application to drug development. Less