D. Accili et al., A TARGETED MUTATION OF THE D-3 DOPAMINE-RECEPTOR GENE IS ASSOCIATED WITH HYPERACTIVITY IN MICE, Proceedings of the National Academy of Sciences of the United Statesof America, 93(5), 1996, pp. 1945-1949
While most effects of dopamine in the brain are mediated by the D-1 an
d D-2 receptor subtypes, other members of this G protein-coupled recep
tor family have potentially important functions. D-3 receptors belong
to the D-2-like subclass of dopamine receptors, activation of which in
hibits 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 recep
tor 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 hyperacti
vity in an exploratory test. Homozygous mice lacking D-3 receptors dis
play increased locomotor activity and rearing behavior. Mice heterozyg
ous for the D-3 receptor mutation show similar, albeit less pronounced
, behavioral alterations. Our findings indicate that D-3 receptors pla
y an inhibitory role in the control of certain behaviors.