Phenotypic studies on dopamine receptor subtype and associated signal transduction mutants: insights and challenges from 10 years at the psychopharmacology-molecular biology interface

Background: Mutants with targeted gene deletion ('knockout') or insertion (transgenic) of D-1, D-2, D-3, D-4 and D-5 dopamine (DA) receptor subtypes are complemented by an increasing variety of double knockout and transgenic-'knockout' models, together with knockout of critical components of DA receptor signalling cascades such as G alpha(olf)[G gamma(7)], adenylyl cyclase type 5, PKA [RII beta] and DARPP-32. However, it is increasingly recognised that these molecular techniques have a number of inherent limitations. Furthermore, there are poorly understood methodological factors that contribute to inconsistent phenotypic findings between laboratories. Objectives: This review seeks to document the impact of DA receptor subtype and related transduction mutants on our understanding of the behavioural roles of these entities, primarily at the level of unconditioned psychomotor behaviour. Methods: It includes ethologically based and orofacial movement studies in our own laboratories, since these are the only studies to systematically compare each of the D-1, D-2, D-3, D-4 and D-5 receptor and DARPP-32 signal transduction 'knock-outs'. Discussion: There is a particular emphasis on identifying methodological factors that might influence phenotypic effects and account for inconsistencies. The findings are offered empirically to (1) specify the extent of phenotypic diversity among individual DA receptor subtypes and transduction components and (2) indicate relationships between D-1, D-2, D-3, D-4 and D-5 receptor subtype proteins, associated G alpha(i)/G alpha(s)/G alpha(olf)[G gamma(7)]-adenylyl cyclase type 5-PKA [RII beta]-DARPP-32 signalling cascades and behaviour. The findings are also offered heuristically as a base for such phenotypic comparisons at additional levels of behaviour so that a yet more complete phenotypic profile might emerge.