Phenotypic, ethologically based resolution of spontaneous and D2‐like vs D1‐like agonist‐induced behavioural topography in mice with congenic D3 dopamine receptor “knockout”

Uncertainty as to the functional role of the D3 dopamine receptor, due primarily to a paucity of selective agonists or antagonists, is being addressed in mice with targeted gene deletion (“knockout”) thereof. This study describes, for the first time, the phenotype of congenic D3‐null mice. Initially, 129/Sv × C57BL/6 D3‐null mice were backcrossed 14 times onto C57BL/6; they were then assessed using an ethologically based approach which resolves all topographies of behaviour within the mouse repertoire. The ethogram of D3‐null mice, on comparison with wildtypes, was characterised by no alteration in any topography of behaviour over an initial period of exploration; subsequent assessment over several hours revealed only increased rearing among females due to delayed habituation. Low doses of the selective D2‐like agonist RU 24213 (0.016–0.25 mg/kg) inhibited topographies of exploratory behaviour; this effect was diminished in D3‐null mice only when investigated following prolonged habituation, and then only for certain topographies of behaviour, primarily sniffing and rearing. High doses of RU 24213 (0.1–12.5 mg/kg) induced stereotyped sniffing and “ponderous” locomotion, while the selective D1‐like agonist SK&F 83959 (0.016–2.0 mg/kg) promoted characteristic grooming syntax; these effects did not differ materially between the genotypes. When examined topographically on an essentially congenic C57BL/6 background (<0.005% 129/Sv), the resultant phenotype indicated essential conservation of the mouse ethogram, high‐dose D2‐like stimulatory effects, and D1‐like stimulatory effects in the absence of D3 receptors. A role for D3 receptors in inhibitory processes appeared topographically circumscribed and only when baseline levels of behaviour were low. Synapse 46:19–31, 2002. © 2002 Wiley‐Liss, Inc.