A targeted mutation of the D-3 dopamine receptor gene is associated with hyperactivity in mice

While most effects of dopamine in the brain are mediated by the D-1 and D-2 receptor subtypes, other members of this G protein-coupled receptor family have potentially important functions. D-3 receptors belong to the D-2-like subclass of dopamine receptors, activation of which inhibits adenylyl cyclase. Using targeted mutagenesis in mouse embryonic stem cells, we have generated mice lacking functional D-3 receptors. A premature chain-termination mutation was introduced in the D-3 receptor gene after residue Arg-148 in the second intracellular loop of the predicted protein sequence. Binding of the dopamine antagonist [I-125] iodosulpride to D-3 receptors was absent in mice homozygous for the mutation and greatly reduced in heterozygous mice. Behavioral analysis of mutant mice showed that this mutation is associated with hyperactivity in an exploratory test. Homozygous mice lacking D-3 receptors display increased locomotor activity and rearing behavior. Mice heterozygous for the D-3 receptor mutation show similar, albeit less pronounced, behavioral alterations. Our findings indicate that D-3 receptors play an inhibitory role in the control of certain behaviors.