Ethological resolution of behavioral topography and D2-like vs. D1-like agonist responses in congenic D4 dopamine receptor "knockouts":: Identification of D4:D1-like interactions

To clarify the involvement of dopamine D-4 receptors in behavioral regulation, the phenotypic ethogram of congenic D-4 "knockout" mice was studied in terms of (i) course of exploration and habituation, and (ii) topographical responsiveness to the selective D-2-like agonist RU 24213 and the selective D-1-like agonists A 68930, SK&F 83959 and SK&F 83822. Congenic D-4 knockouts were characterized by a small reduction in exploratory sniffing with delayed habituation of sifting. The magnitude and topographical specificity of these effects indicated that any functional role for D-4 receptors in exploratory processes is subtle. Induction of stereotyped, ponderous locomotion by RU 24213 was reduced in D-4-null mice consistent with an involvement of D-4 receptors in the topographical expression of stereotypy. Induction of grooming and, at higher doses, seizures by A 68930, which stimulates both adenylyl cyclase (AC) and phospholipase C (PLC), were unaltered in congenic D-4 knockouts. In contrast, induction of grooming by SK&F 83959, which stimulates PLC but not AC and fails to induce seizures, was reduced in D4-null mice; this indicates that D-4 receptors interact with PLC-coupled D-1-like receptors in regulating D-1-like-mediated grooming. Conversely, induction of seizures by SK&F 83822, which stimulates AC but not PLC and fails to induce grooming, was reduced in congenic D-4 knockouts; this indicates that D-4 receptors interact with AC-coupled D-1-like receptors in regulating D-1-like-mediated seizures. These studies identify novel functional roles for the D-4 receptor that are distinct from those of closely related D-2-like family members and involve interactions with their D-1-like counterparts.