Neurobiology of Central D1-Dopamine Receptors (Advances in Experimental Medicine and Biology, 204)

Our understanding of the functional mechanisms relating dopamine activity to normal and abnormal behavior has been turned "upside-down" by the recent developments described in the chapters of this volume. Heretofore, it was generally agreed that all of the pharmacological and behavioral properties ascribed to dopamine systems were mediated via activation or inhibition of the subtype of dopamine receptors termed D2. The properties of these receptors were first characterized in 1975 following their identification by receptor binding techniques utilizing 3H-butyrophenones, potent antipsychotic drugs, used in the treatment of schizophrenia. Although another subtype of dopamine receptor had already been identified a few years earlier, now termed the Dl receptor, its functional properties were unknow- other than the fact that it was associated with the activation of the enzyme adenylate cyclase. Our absence of knowledge of the behavioral functions of this receptor stemmed primarily from the lack of selective agonist and antagonists for DI receptors - drugs which did not also interact with D2 receptors. Selective agents for D2 receptors did exist and hence the behavioral roles of D2 receptors were easily ascribed. The work described in this text is primarily stimulated by the development of two selective Dl receptor drugs - the antagonist SCH 23390 and the agonist SKF 38393. The studies described herein clearly show that D1 receptors do indeed have many behavioral functions, on the surface often similar to those responses mediated by D2 receptors. Our understanding of the functional mechanisms relating dopamine activity to normal and abnormal has been turned "upside-down" by the recent developments described in agreed that all of the pharmacological and behavioral properties ascribed to dopamine receptors termed D2. The properties of these receptors were first characterized in 1975 following their identification by receptor binding techniques utilizing 3H-butyrophenones, potent antipsychotic drugs, used in the treatment of schizophrenia. Although another subtype of dopamine receptors had already been identified a few years earlier, now termed the D1 receptor, its functional properties were unknown - other than the fact that it was associated with the activation of the enzyme adenylate cyclase. Our absence of knowledge of the behavioral functions of this receptor stemmed primarily from the lack of selective agonist and antagonists for D1 receptors - drugs which did not also interact with D2 receptors. Selective agents for D2 receptors did exist and hence the behavioral roles of D2 receptors were easily ascribed. The work described in this text is primarily stimulated by the development of two selective D1 receptor drug - the antagonist SCH 23390 and the agonist SKF 38393. The studies described herein clearly show that D1 receptors do indeed have many behavioral functions, on the surface often similar to those responses mediated by D2 receptors. These observations hold hope for the development of new dopaminergic agents for use in the treatment of psychiatric and neurologic diseases that may by more selective in their actions and lack some of the side effects of the presently used mixed of D2 receptor selective agents. These studies are the beginning of an active period of new research strategies that will provide a greater understanding of the role of dopamine systems in behavior. Front Matter....Pages i-viii Benzazepines: Structure-Activity Relationships Between D 1 Receptor Blockade and Selected Pharmacological Effects....Pages 1-14 Characterization of Dopamine D-1 and D-2 Receptors....Pages 15-28 Biochemical and Behavioral Studies of D 1 Dopamine Receptors Utilizing SCH 23390....Pages 29-52 The Multiplicity of the D 1 Dopamine Receptor....Pages 53-72 The Dopamine D 1 Receptor: Biochemical and Behavioral Aspects....Pages 73-91 Quantitative Autoradiographic Localization of Central Dopamine D-1 and D-2 Receptors....Pages 93-118 Dopamine D 1 -Receptor Binding in the Living Human Brain....Pages 119-124 Enantiomeric Analogues of SCH 23390 as New Probes for Behavioral Interactions between D 1 and D 2 Dopaminergic Function....Pages 125-136 Functional Interactive Effects of D 1 and D 2 Dopamine Receptor Blockade....Pages 137-150 Interaction of D 1 and D 2 Dopamine Receptors in the Expression of Dopamine Agonist Induced Behaviors....Pages 151-166 Electrophysiological Assessment of Dopamine Receptor Subtypes....Pages 167-188 The Pathophysiological Functions Mediated by D 1 Dopamine Receptors....Pages 189-195 Neurobiology of D 1 Dopamine Receptors after Neonatal-6-OHDA Treatment: Relevance to Lesch-Nyhan Disease....Pages 197-215 Back Matter....Pages 217-219