Conservation of behavioural topography to dopamine D 1-like receptor agonists in mutant mice lacking the D 1A receptor implicates a D 1-like receptor not coupled to adenylyl cyclase

Abstract

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 functionally prepotent subtype, evidence suggests the existence of another, novel D 1-like receptor without such coupling. To investigate these issues we challenged mutant mice having targeted gene deletion of the D 1A receptor with selective agonists and used an ethologically-based assessment technique to resolve resultant behavioural topography. D 1-like-dependent behaviour was substantially conserved in D 1A-null mice relative to wild-types following 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 dopamine. 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 integrity 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 other than D 1A [or D 1B] that is coupled to a transduction system other than/additional to adenylyl cyclase.