STUDY OF ROLES OF TACHYKININS IN THE NERVOUS SYSTEM

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Substance P (SP) has been shown in certain systems to modulate the actions of acetylcholine and norepinephrine. Although modulation of the effects of classic neurotransmitters may be one of the important functions of SP in the nervous system, the mechanisms by which it does this are unknown. SP was the first member of the tachykinin family to be identified in the brain. Recently two new tachykinins, neurokinin A (NKA) and neurkinin B (NKB), were identified in mammalian nervous tissue. Detailed anatomical distributions of NKA and NKB and their binding sites remains unknown. It is also not known whether NKA and NKB have modulatory actions of their own. Polyclonal antisera will be raised in rabbits against NKA and NKB, and their distributions in rat brain will be studied by both microdissection combined with radioimmunoassay and by immunshistochemistry. We will determine if NKA and NKB ae present in human brain and, if so, in which regions. Because SP is reduced in Parkinson's, Huntington's, and Alzheimer's diseases, we will determine whether levels of NKA and NKB are also changed in these diseases. The binding sites for NKA and NKB in rat brain will be characterized by membrane and slice binding techniques and localized by autoradiography. In cultured rat astrocytes SP augments norepinephrine's stimulation of cAMP formation without stimulating cAMP production itself. Cultured astrocytes will be developed as a system to systematically study mechanisms of tachykinin modulation of beta adrenergic stimulated increase in cAMP. Binding studies both in intact cells and with membranes will be performed to assess the effects of tachykinins on the affinity and number of beta adrenergic receptors. The effect of tachykinins on the activity of adenylate cyclase, phosphodiesterase, and phosphoinositide metabolism will also be studied. Our findings from astrocytes will be applied to brain regions in which significant levels of tachykinins or their binding sites are found to study the biochemical mechanism of tachykinin action in the brain. One member of the tachykinin family, SP, is acknowledged to play a significant role in the extrapyramidal and nociceptive systems. SP has also been shown to be decreased in certain degenerative neurological diseases. The proposed studies will elucidate regions of the brain in which tachykinins are involved in neurological function and dysfunction and biochemical mechanisms by which they act.