The psychopharmacology-molecular biology interface: exploring the behavioural roles of dopamine receptor subtypes using targeted gene deletion (‘knockout’)

Comparative, Topographically-Based Evaluation of Behavioural Phenotype and Specification of D1-Like:D2 Interactions in a Line of Incipient Congenic Mice with D2 Dopamine Receptor 'Knockout'

“…This habituation ethogram for the D 2 knockout line of Kelly et al (1998) is also similar to that which we have described previously for the D 2 knockout line of Baik et al (1995); indeed, juxtaposition of data in the present Figure 2 with comparable data in Figure 2 of Clifford et al (2000) attests the similarity of phenotype for these two D 2 knockout lines at an additional level of behavioural examination. Also, these data emphasise a critical functional dissociation from the phenotype of D 1A knockouts, for which the habituation phase revealed the emergence of important phenotypic differences which were not evident over initial exploration ; thus, the present data sustain and elaborate the notion that D 1A but not D 2 receptors interact with the neuronal substrate of habituation in 'sculpting' the changing topography of behaviour from initial exploration through to quiescence Waddington et al 2001).…”

“…This study seeks to compare two independently derived lines of D 2 receptor-deficient mice (Baik et al 1995;Kelly et al 1998) under essentially identical testing conditions, in an effort to differentiate those phenotypic differences which are the result of targeting this particular DA receptor subtype from those that are manifestations of other parameters (e.g., differences between strains and testing paradigms); it should be re- called that these two laboratories utilised different genetic constructs on a varying genetic background, with examination of behavioural phenotype using diverse procedures, each of these factors being capable of influencing knockout phenotype independent of the entity deleted (Picciotto 1999;Crawley 1999;Gerlai 1999;Crabbe et al 1999;Waddington et al 2001).…”

“…Over recent years, several groups have applied recombinant DNA technology to construct mice with targeted gene deletion ['knockout'] of individual dopamine receptor subtypes (Sibley 1999;Waddington et al 2001), and three of these have concerned the D 2 subtype (Baik et al 1995;Kelly et al 1997Kelly et al , 1998Jung et al 1999). Although different genetic strategies were utilised, all three groups demonstrated comparable neurochemical evidence that functional D 2 receptors had been ablated.…”

“…It is important to note that each of these laboratories utilised a different genetic construct on a distinct genetic background, with examination of behavioural phenotype using diverse procedures, each of these factors being capable of influencing phenotype independent of the entity deleted (Crawley 1999;Gerlai 1999;Crabbe et al 1999;Picciotto 1999;Waddington et al 2001). Indeed, the studies of Kelly et al (1998) suggest a material contribution from differences in genetic background to the diversity of findings between laboratories in relation to the behavioural phenotype of D 2 knockout.…”

Simultaneous absence of dopamine D1 and D2 receptor-mediated signaling is lethal in mice

“…Pharmacological studies have not allowed a full understanding of the specific role of each DA receptor in vivo because of the lack of ligands with absolute receptor specificity. Knockout mice for each DA receptor have now been reported (1)(2)(3)(4)(5)(6)(7)(8)(9), substantially increasing our knowledge of the dopaminergic system (10,11).…”