REGIONAL BLOOD-BRAIN BARRIER TRANSPORT OF AMINO ACIDS

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The brain is critically dependent on the circulating blood for a supply of essential nutrients: glucose and ketone bodies for energy metabolism, amino acids for protein and neurotransmitters, choline for acetylcholine, and nucleosides, purines and pyrimidines for nucleotides, RNA, and DNA. The rate-limiting step for entry of each of these compounds appears to be passage across the blood-brain barrier, which is mediated by saturable transport processes obeying Michaelis-Menten kinetics. The blood-brain barrier transport systems are in a unique position to regulate the entry of essential nutrients and thereby affect brain function. It has been established at least in one pathological condition, hepatic encephalopathy, that the transport of different classes of nutrients are altered in a characteristic way. There is good reason to believe that transport in other pathological states such as diabetes, hypothyroidism, and uremia, will also be changed. Until recently, all studies examining blood-brain barrier transport have been conducted in whole brain. Further advances in our knowledge of brain function require the understanding of these processes at the structural level, and methods for achieving this have been established. It is the purpose of this proposal to study the local transport of various essential substrates at the level of individual brain structures using an autoradiographic technique developed in the principal investigator's laboratory. The primary effort will be to study the distribution of transport systems in several pathological situations including hypothyroidism, uremia, and diabetes. The data will allow the determination of the location and magnitude of changes in the blood-brain barrier and make possible the evaluation of their relevance to the disease process.