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 D ₂-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 D ₄ 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.