1. ¹Department of Clinical Pharmacology, Royal College of Surgeons in Ireland, Dublin, Ireland
2. ²Institute of Biopharmaceutical Sciences, Royal College of Surgeons in Ireland, Dublin, Ireland
3. ³Department of Biochemistry, Royal College of Surgeons in Ireland, Dublin, Ireland
4. ⁴School of Mathematics, Dublin Institute of Technology, Dublin, Ireland
5. ⁵Department of Medicine, Monash University, Monash Medical Center, Victoria, Australia

Correspondence: Dr JL Waddington, Department of Clinical Pharmacology, Royal College of Surgeons in Ireland, St Stephen's Green, Dublin 2, Ireland. Tel: +353 1 402 2245; Fax: +353 1 402 2453; E-mail: jwadding@rcsi.ie

Received 28 February 2002; Revised 6 June 2002; Accepted 12 June 2002.

Abstract

D_1A-null mice were backcrossed over 14 generations into a C57BL/6 background to result in essential elimination (to <0.005%) of any contribution from the 129/Sv component of their initially mixed (129/SvC57BL/6) background. Their phenotype was assessed using an ethologically based approach that resolves each individual topography of behaviour in the natural repertoire. Habituation of sniffing, locomotion, rearing seated, and rearing to wall in wild types over several hours was profoundly retarded in congenic D_1A mutants; conversely, rearing free and sifting were essentially abolished. Resultant increases in individual topographies of behaviour were substantially greater in congenic D_1A mutants than in those on a mixed background. This phenotype was little altered by the selective D₁-like antagonist SCH 23390 and could not be blocked by the selective D₂-like antagonist YM 09151-2. The selective D₁-like agonist SK&F 83959 could not further elevate those behaviours already heightened in congenic D_1A mutants, while the induction of stereotyped sniffing and plodding locomotion by the selective D₂-like agonist RU 24213 was disrupted. Genetic background appears to modulate critically the magnitude but not the general nature of the D_1A-null phenotype, which may involve compensatory processes independent of other D₁-like or D₂-like receptors.