Ethological resolution of behavioral topography and D 2 ‐like vs. D 1 ‐like agonist responses in congenic D 4 dopamine receptor “knockouts”: Identification of D 4 :D 1 ‐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 D 4 ‐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. Synapse 59:107–118, 2006. © 2005 Wiley‐Liss, Inc.