1. ¹Department of Pharmacology, Faculty of Medicine, Monash University, Clayton, VIC, Australia
2. ²Institut de Recherche Interdisciplinaire, Faculte de Medecine, Universite de Bruxelles, Brussels, Belgium
3. ³Howard Florey Institute, University of Melbourne, Parkville, VIC, Australia

Correspondence: Dr AJ Lawrence, Brain Injury & Repair Group, Howard Florey Institute, Royal Parade, Parkville, Victoria 3010, Australia. Tel: + 613 8344 0414; Fax: + 613 9348 1707; E-mail: Andrew.Lawrence@hfi.unimelb.edu.au

Received 10 November 2004; Revised 3 June 2005; Accepted 23 June 2005; Published online 10 August 2005.

Abstract

Here we report the development of D₁A_2A receptor knockout mice to investigate whether interactions between dopamine D₁ and adenosine A_2A receptors participate in reward-related behavior. The combined deletion of D₁ and A_2A receptors resulted in mice with decreased weight and appetitive processes, reduced rearing and exploratory behaviors, increased anxiety, and a significantly poorer performance on the rotarod, compared to wild-type littermates. D₁A_2A receptor knockout mice shared phenotypic similarities with mice deficient in D₁ receptors, while also paralleling behavioral deficits seen in A_2A receptor knockout mice, indicating individual components of the behavioral phenotype of the D₁A_2A receptor knockout attributable to the loss of both receptors. In contrast, ethanol and saccharin preference in D₁A_2A receptor knockout mice were distinctly different from that observed in derivative D₁ or A_2A receptor-deficient mice. Compared to wild types, preference and consumption of ethanol were decreased in D₁A_2A receptor knockout mice, the reduction in ethanol consumption greater even than that seen in D₁ receptor-deficient mice. Preference and consumption of saccharin were also reduced in D₁A_2A receptor knockout mice, whereas saccharin preference was similar in wild-type, D₁, and A_2A receptor knockout mice. These data suggest an interaction of D₁ and A_2A receptors in the reinforcement processes underlying the intake of rewarding substances, whereby the A_2A receptor seems involved in goal-directed behavior and the motor functions underlying the expression of such behaviors, and the D₁ receptor is confirmed as essential in mediating motivational processes related to the repeated intake of novel substances and drugs.