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 D4 receptors in behavioral regulation, the phenotypic ethogram of congenic D4 "knockout" mice was studied in terms of (i) course of exploration and habituation, and (ii) topographical responsiveness to the selective D2-like agonist RU 24213 and the selective D1-like agonists A 68930, SK&F 83959 and SK&F 83822. Congenic D4 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 D4 receptors in exploratory processes is subtle. Induction of stereotyped, ponderous locomotion by RU 24213 was reduced in D4-null mice consistent with an involvement of D4 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 D4 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 D4 receptors interact with PLC-coupled D1-like receptors in regulating D1-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 D4 knockouts; this indicates that D4 receptors interact with AC-coupled D1-like receptors in regulating D1-like-mediated seizures. These studies identify novel functional roles for the D4 receptor that are distinct from those of closely related D2-like family members and involve interactions with their D1-like counterparts.