The long term objective of this proposal is to increase our understanding of the psychopharmacology of neuropeptides in general, substance P and other tachykinins in particular. Since there are strong indications that substance P (SP) is involved in the effects of antidepressant agents, we will characterize the different tachykinin receptors to gain insight into their role in health and disease.
The specific aims of this project are the following: 1. Characterization of the substance P and other tachykinin receptors in the central nervous system. We will continue with our studies of the SP-P receptor using (3H)physalaemin, and neurokinin A (substance K) to determine the biochemical characteristics of the SP-E receptor subtype. Briefly, we will: a) Determine the equilibrium and kinetic constants of labeled tachykinins for the different central nervous system receptors. b) Characterize the different receptor subtypes by studying the relative potency of competing agonists and antagonists. c) Determine the sensitivity of the different receptors to protein-modifying reagents and enzymes. d) Study the subcellular and regional distribution of the different receptors. 2. Determination of the role of the guanine nucleotide binding protein associated with substance P and other tachykinin receptors. To study the role of the GTP-binding regulatory protein of the tachykinin receptors we will: a) Determine the effect of divalent cations and guanine nucleotides. b) Examine the effects of protein-modifying reagents and enzymes. c) Subject the GTP-binding regulatory protein to ADP-ribosylation with cholera and pertussis toxins. 3. To investigate the relationships between substance P receptor and antidepressants and lithium, we will: Determine the effects of a) chronic administration of antidepressant drugs and b) chronic administration of lithium, on the affinity and number of substance P and other tachykinin receptors in the rat brain.
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