Conservation of behavioural topography to dopamine D-1-like receptor agonists in mutant mice lacking the D-1A receptor implicates a D-1-like receptornot coupled to adenylyl cyclase

Though D-1-like dopamine receptors [D-1A/B] are defined in terms of linkage to the stimulation of adenylyl cyclase, with D-1A assumed to be the functi onally prepotent subtype, evidence suggests the existence of another, novel D-1-like receptor without such coupling. To investigate these issues we ch allenged mutant mice having targeted gene deletion of the D-1A receptor wit h selective agonists and used an ethologically-based assessment technique t o resolve resultant behavioural topography. D-1-like-dependent behaviour wa s substantially conserved in D-1A-null mice relative to wild-types followin g challenge with each of two selective D-1-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 dopami ne. Furthermore, responsivity to the selective D-2-like agonist RU 24213 (0 .1-12.5 mg/kg s.c.) was conserved in D-1A-null mice, indicating the integri ty of D-1-like:D-2-like interactions at the level of behaviour. These data are consistent with behavioural primacy of a D-1-like receptor o ther than D-1A [or D-1B] that is coupled to a transduction system other tha n/additional to adenylyl cyclase. (C) 1999 IBRO. Published by Elsevier Scie nce Ltd.