Conservation of behavioural topography to dopamine D1-like receptor agonists in mutant mice lacking the D1A receptor implicates a D1-like receptor not coupled to adenylyl cyclase.
Though D1-like dopamine receptors [D1A/B] are defined in terms of linkage to the stimulation of adenylyl cyclase, with D1A assumed to be the functionally prepotent subtype, evidence suggests the existence of another, novel D1-like receptor without such coupling. To investigate these issues we challenged mutant mice having targeted gene deletion of the D1A receptor with selective agonists and used an ethologically-based assessment technique to resolve resultant behavioural topography. D1-like-dependent behaviour was substantially conserved in D1A-null mice relative to wild-types following challenge with each of two selective D1-like agents: A 68930 (0.068-2.0 mg/kg s.c.) which exhibits full efficacy to stimulate adenylyl cyclase, and SKF 83959 (0.016-2.0 mg/kg s.c.) which fails to stimulate adenylyl cyclase, and indeed inhibits the stimulation of adenylyl cyclase induced by dopamine. Furthermore, responsivity to the selective D2-like agonist RU 24213 (0.1-12.5 mg/kg s.c.) was conserved in D1A-null mice, indicating the integrity of D1-like:D2-like interactions at the level of behaviour. These data are consistent with behavioural primacy of a D1-like receptor other than D1A [or D1B] that is coupled to a transduction system other than/additional to adenylyl cyclase.
Clifford
J J
JJ
Department of Clinical Pharmacology, Royal College of Surgeons in Ireland, St Stephen's Green, Dublin.
Tighe
O
O
Croke
D T
DT
Kinsella
A
A
Sibley
D R
DR
Drago
J
J
Waddington
J L
JL
D015647:2,3,4,5-Tetrahydro-7,8-dihydroxy-1-phenyl-1H-3-benzazepine / Q000031:analogs & derivatives / Q000494:pharmacology; D000262:Adenylyl Cyclases / Q000378:metabolism*; D000818:Animals; D001522:Behavior, Animal / Q000187:drug effects*; D001921:Brain / Q000201:enzymology; D001923:Brain Chemistry; D002839:Chromans / Q000494:pharmacology; D018491:Dopamine Agonists / Q000494:pharmacology; D005260:Female; D006120:Grooming / Q000187:drug effects; D008124:Locomotion / Q000187:drug effects; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D010627:Phenethylamines / Q000494:pharmacology; D017447:Receptors, Dopamine D1 / Q000819:agonists* / Q000235:genetics*; D017448:Receptors, Dopamine D2 / Q000819:agonists / Q000502:physiology
D002839:Chromans; D018491:Dopamine Agonists; D010627:Phenethylamines; D017447:Receptors, Dopamine D1; D017448:Receptors, Dopamine D2; 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; C065380:A 68930; D000262:Adenylyl Cyclases