Congenic D1A dopamine receptor mutants: ethologically based resolution of behavioural topography indicates genetic background as a determinant of knockout phenotype.
D(1A)-null mice were backcrossed over 14 generations into a C57BL/6 background to result in essential elimination (to <0.005%) of any contribution from the 129/Sv component of their initially mixed (129/SvxC57BL/6) background. Their phenotype was assessed using an ethologically based approach that resolves each individual topography of behaviour in the natural repertoire. Habituation of sniffing, locomotion, rearing seated, and rearing to wall in wild types over several hours was profoundly retarded in congenic D(1A) mutants; conversely, rearing free and sifting were essentially abolished. Resultant increases in individual topographies of behaviour were substantially greater in congenic D(1A) mutants than in those on a mixed background. This phenotype was little altered by the selective D(1)-like antagonist SCH 23390 and could not be blocked by the selective D(2)-like antagonist YM 09151-2. The selective D(1)-like agonist SK&F 83959 could not further elevate those behaviours already heightened in congenic D(1A) mutants, while the induction of stereotyped sniffing and plodding locomotion by the selective D(2)-like agonist RU 24213 was disrupted. Genetic background appears to modulate critically the magnitude but not the general nature of the D(1A)-null phenotype, which may involve compensatory processes independent of other D(1)-like or D(2)-like receptors.
McNamara
Fergal N
FN
Department of Clinical Pharmacology, Royal College of Surgeons in Ireland, Dublin.
Clifford
Jeremiah J
JJ
Tighe
Orna
O
Kinsella
Anthony
A
Drago
John
J
Croke
David T
DT
Waddington
John L
JL
D015647:2,3,4,5-Tetrahydro-7,8-dihydroxy-1-phenyl-1H-3-benzazepine / Q000031:analogs & derivatives* / Q000494:pharmacology; D000818:Animals; D020296:Animals, Congenic; D001522:Behavior, Animal / Q000502:physiology*; D001549:Benzamides / Q000494:pharmacology; D001552:Benzazepines / Q000494:pharmacology; D018491:Dopamine Agonists / Q000494:pharmacology; D018492:Dopamine Antagonists / Q000494:pharmacology; D005106:Exploratory Behavior / Q000502:physiology; D006185:Habituation, Psychophysiologic; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009043:Motor Activity / Q000187:drug effects; D009154:Mutation / Q000502:physiology*; D010627:Phenethylamines / Q000494:pharmacology; D010641:Phenotype; D017447:Receptors, Dopamine D1 / Q000819:agonists / Q000037:antagonists & inhibitors / Q000235:genetics*; D019076:Transgenes / Q000235:genetics
D001549:Benzamides; D001552:Benzazepines; D018491:Dopamine Agonists; D018492:Dopamine Antagonists; D010627:Phenethylamines; D017447:Receptors, Dopamine D1; C098593:dopamine D1A receptor; 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; C030265:nemonapride