Localization and characterization of dopamine D-1 receptors in the central nervous system.

Dopamine, a central nervous system neurotransmitter, is considered to be intimately involved in a variety of functions including both behavior and movement. This catecholamine mediates its effects via at least two dopamine receptor populations designated dopamine type one (D-1) and dopamine type two (D-2). Recently, a novel benzazepine, SCH 23390 (R)-(+)-8 chloro-2,3,4,5-tetrahydro-3-methyl-5-phenyl-1H-3-benzazepine-7-ol , has been described as a potent D-1 receptor antagonist. The quantitative technique of in vitro receptor autoradiography, after labeling tissue sections with ('3)H -SCH 23390 or ('125)I -SCH 23982 (a potent D-1 receptor antagonist), was applied to localize receptor populations for the D-1 receptor. Furthermore, the distribution and density of D-1 receptors was compared to that of the D-2 receptor labeled with ('3)H -sulpiride. The binding of ('3)H -SCH 23390 or ('125)I -SCH 23982 to slide-mounted tissue sections takes place with characteristics expected of a substance which is recognizing D-1 receptors. The binding in rat brain is saturable, has high affinity, and exhibits an appropriate pharmacology and stereospecificity in several discrete microscopic brain regions as determined by quantitative autoradiography. In the rat brain, the highest density of D-1 receptors occurs in the caudate-putamen, accumbens nucleus, olfactory tubercle, and the substantia nigra pars reticulata. High concentrations of D-1 receptors were demonstrated to be associated with the intercalated and medial nuclei of the amygdala, entopeduncular nucleus and the major island of Calleja. Furthermore, moderate to low concentrations were observed in several other structures such as the frontal cortex, subthalamic nucleus and several thalamic, hypothalamic and hippocampal areas. The distribution of D-1 receptors in the rat brain correlates very well with projection areas of dopaminergic pathways. These results provide a powerful insight into the mechanisms of action of drugs which act on dopamine receptors and provide additional support for two pharmacologically distinct dopamine receptors in the brain. The localization of D-1 receptors will hopefully help elucidate more of the physiologic functions associated with this receptor subtype, and indicate areas where additional biochemical and neuroanatomical studies may be performed to ultimately lead to a better understanding of central dopamine systems.

THE UNIVERSITY OF UTAH GRADUATE SCHOOL SUPERVISORY COMMITTEE APPROVAL of a dissertation submitted by Ted Hurray Dawson This dissertation has been read by each member of the following supervisory committee and by majority vote has been found to be satisfactory. Donald N. Franz � �- i Z. / ........, , -ft- Bernard I. Grosser " 1;/-' -' Glen R. Hanson THE UNIVERSITY OF UTAH GRADUATE SCHOOL FINAL READING APPROVAL To the Graduate Council of The University of Utah: I have read the dissertation of Ted Hurray Dawson m ItS final form and have found that (1) its format, citations. and bibliographic style are consistent and acceptable; (2) its illustrative materials including figures, tables, and charts are in place; and (3) the final manuscript is satisfactory to the Supervis­ ory Committee and is ready for submission to the Graduate School. Date } James 0 / K.; Hamsley ,r-- L£hairperson, Su pervisory Committee Approved for the Major Department Idl Do J. Reed Chairman I Dean Approved for [he Graduate Council ::: Graduate School