title: Phenotypic, ethologically based resolution of spontaneous and D(2)-like vs D(1)-like agonist-induced behavioural topography in mice with congenic D(3) dopamine receptor "knockout".
abstract: Uncertainty as to the functional role of the D(3) 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 D(3)-null mice. Initially, 129/Sv x C57BL/6 D(3)-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 D(3)-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 D(2)-like agonist RU 24213 (0.016-0.25 mg/kg) inhibited topographies of exploratory behaviour; this effect was diminished in D(3)-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 D(1)-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 D(2)-like stimulatory effects, and D(1)-like stimulatory effects in the absence of D(3) receptors. A role for D(3) receptors in inhibitory processes appeared topographically circumscribed and only when baseline levels of behaviour were low.
authors.affiliation: Department of Clinical Pharmacology, Royal College of Surgeons in Ireland, Dublin 2, Ireland.
authors.forename: Fergal N
authors.initials: FN
authors.lastname: McNamara
authors.forename: Jeremiah J
authors.initials: JJ
authors.lastname: Clifford
authors.forename: Orna
authors.initials: O
authors.lastname: Tighe
authors.forename: Anthony
authors.initials: A
authors.lastname: Kinsella
authors.forename: John
authors.initials: J
authors.lastname: Drago
authors.forename: Sara
authors.initials: S
authors.lastname: Fuchs
authors.forename: David T
authors.initials: DT
authors.lastname: Croke
authors.forename: John L
authors.initials: JL
authors.lastname: Waddington
mesh_terms: D015647:2,3,4,5-Tetrahydro-7,8-dihydroxy-1-phenyl-1H-3-benzazepine / Q000031:analogs & derivatives* / Q000494:pharmacology; D000818:Animals; D001522:Behavior, Animal / Q000187:drug effects*; D018491:Dopamine Agonists / Q000494:pharmacology; D005106:Exploratory Behavior / Q000187:drug effects; D005260:Female; D006185:Habituation, Psychophysiologic / Q000187:drug effects; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D010627:Phenethylamines / Q000494:pharmacology; D010641:Phenotype; D017447:Receptors, Dopamine D1 / Q000819:agonists* / Q000378:metabolism; D017448:Receptors, Dopamine D2 / Q000819:agonists* / Q000235:genetics* / Q000378:metabolism; D050637:Receptors, Dopamine D3
chemical_list: D018491:Dopamine Agonists; C493594:Drd3 protein, mouse; D010627:Phenethylamines; D017447:Receptors, Dopamine D1; D017448:Receptors, Dopamine D2; D050637:Receptors, Dopamine D3; D015647:2,3,4,5-Tetrahydro-7,8-dihydroxy-1-phenyl-1H-3-benzazepine; C016868:N-n-propyl-N-phenylethyl-4(3-hydroxyphenyl)ethylamine hydrochloride; C080703:SK&F 83959