Ethological resolution of behavioural topography and D1-like versus D2-like agonist responses in congenic D5 dopamine receptor mutants: identification of D5:D2-like interactions.
The phenotypic ethogram of congenic dopamine D(5) 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 D(1)-like agonists. Over initial exploration, D(5)-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 D(1)-like agonists, A 68930 stimulates both adenylyl cyclase and a putative D(1)-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 D(5) mutants. Stereotyped, ponderous locomotion induced by the D(2)-like agonist RU 24213 was enhanced in D(5) mutants. Phenotypic and pharmacological characterisation of congenic D(5)-null mice at an ethological level identifies novel functional roles for the D(5) 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 D(5):D(2)-like interactions in regulating these processes.
O'Sullivan
Gerard J
GJ
Department of Clinical Pharmacology and Institute of Biopharmaceutical Sciences, Royal College of Surgeons in Ireland, Dublin 2, Ireland.
Kinsella
Anthony
A
Sibley
David R
DR
Tighe
Orna
O
Croke
David T
DT
Waddington
John L
JL
D000262:Adenylyl Cyclases / Q000378:metabolism; D000818:Animals; D001522:Behavior, Animal / Q000187:drug effects / Q000502:physiology*; D001921:Brain / Q000187:drug effects / Q000378:metabolism*; D001923:Brain Chemistry / Q000187:drug effects / Q000235:genetics*; D018491:Dopamine Agonists / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D005260:Female; D006120:Grooming / Q000187:drug effects / Q000502:physiology; D006185:Habituation, Psychophysiologic / Q000187:drug effects / Q000235:genetics; D006868:Hydrolysis / Q000187:drug effects; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009043:Motor Activity / Q000187:drug effects / Q000235:genetics; D010641:Phenotype; D010716:Phosphatidylinositols / Q000378:metabolism; D017447:Receptors, Dopamine D1 / Q000819:agonists / Q000235:genetics* / Q000378:metabolism; D017448:Receptors, Dopamine D2 / Q000819:agonists / Q000378:metabolism; D050641:Receptors, Dopamine D5
D018491:Dopamine Agonists; C493606:Drd5 protein, mouse; D010716:Phosphatidylinositols; D017447:Receptors, Dopamine D1; D017448:Receptors, Dopamine D2; D050641:Receptors, Dopamine D5; D000262:Adenylyl Cyclases