The long-term goal of the proposed project is the elucidation of the biochemical mechanisms underlying the regulation of histamine synthesis and examination of the consequences of histamine action at its receptors in brain. A variety of evidence indicates that brain histamine turns over rapidly and that its synthesis is regulated by neuronal activity in order to maintain appropriate levels. Regulation of histamine decarboxylase, the sole enzyme involved in histamine biosynthesis, will be studied. This investigation will have a general applicability to the study of other neurotransmitter synthesizing enzymes in the central nervous system. Regulation will be examined in brain slices and synaptosomes to determine the nature of the changes in histidine decarboxylase activity elicited by K ion - depolarization. In addition, studies on the purification, characterization and analysis of regulation of histidine decarboxylase in a partially purified or purified state are planned. The possibility that the enzyme is regulated by protein phosphorylation mediated by cyclic nucleotide-dependent protein kinases as well as the newly-discovered Ca 2 ion-dependent protein kinase will be tested. The effect of histamine acting at H1- and H2-receptors on elevation of cAMP and cGMP will be examined. A variety of psychotropic drugs have been shown to be potent antagonists of the histamine-sensitive adenylate cyclase. The effect of these drugs on histamine-elicted changes in cAMP and cGMP will be tested to determine in a physiological system whether both H1- and H2-receptors are affected by the drugs.