RU-24213

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.

The phenotypic ethogram of congenic dopamine D5 receptor “knockout” mice was evaluated. Each individual topography of behaviour within the natural repertoire was assessed over the extended course of initial exploration of and subsequent habituation to the environment, and following challenge with a series of D1‐like agonists. Over initial exploration, D5‐null mice evidenced a modest reduction in locomotion and a modest increase in sifting. Subsequent habituation revealed additional phenotypic effects, primarily overall reduction in grooming and delayed habituation of rearing. Among D1‐like agonists, A 68930 stimulates both adenylyl cyclase and a putative D1‐like receptor coupled to stimulation of phospholipase C‐mediated phosphoinositide hydrolysis; conversely, SK&F 83959 stimulates phosphoinositide hydrolysis but not adenylyl cyclase while SK&F 83822 stimulates adenylyl cyclase but not phosphoinositide hydrolysis. Though programmed grooming syntax and episodic seizure activity induced by A 68930 and SK&F 83822 were unaltered, grooming induced by SK&F 83959 was reduced in D5 mutants. Stereotyped, ponderous locomotion induced by the D2‐like agonist RU 24213 was enhanced in D5 mutants. Phenotypic and pharmacological characterisation of congenic D5‐null mice at an ethological level identifies novel functional roles for the D5 receptor in mediating discrete topographies of behaviour relating to exploration, sequential motor coordination, and how these processes change over the course of interaction with and habituation to the environment. Additionally, they indicate the involvement of phosphoinositide hydrolysis and D5:D2‐like interactions in regulating these processes. Synapse 55:201–211, 2005. Published 2005 Wiley‐Liss, Inc.