Dopamine (DA) controls a wide variety of physiological functions in the central nervous system as well as in the neuroendocrine and gastrointestinal systems. DA signaling is mediated by five cloned receptors named D1-D5. Knockout mouse models for the five receptors have been generated, and, albeit impaired for some important DA-mediated functions, they are viable and can reproduce. D1 and D2 receptors are the most abundant and widely expressed DA receptors. Cooperative͞synergistic effects mediated by these receptors have been suggested, in particular, in the control of motor behaviors. To analyze the extent of such interrelationship, we have generated double D1͞D2 receptor mutants. Interestingly, in contrast to single knockouts, we found that concurrent ablation of the D1 and D2 receptors is lethal during the second or third week after birth. This dramatic phenotype is likely to be related to altered feeding behavior and dysfunction of the gastrointestinal system, especially because major anatomical changes were not identified in the brain. Similarly, in the absence of functional D1, heterozygous D2 mutants (D1r ؊/؊ ;D2r ؉/؊ ) showed severe growth retardation and did not survive their postweaning period. The analysis of motor behavior in D1r͞D2r compound mutants showed that loss of D2-mediated functions reduces motor abilities, whereas the effect of D1r ablation on locomotion strongly depends on the experimental paradigms used. These studies highlight the interrelationship between D1 and D2 receptor-mediated control of motor activity, food intake, and gastrointestinal functions, which has been elusive in the singlegene ablation studies.knockout mice ͉ motor function ͉ feeding behavior ͉ gastrointestinal system T he diverse physiological functions of dopamine (DA) are mediated by five distinct receptors, which by structural and pharmacological means have been grouped into two families: the D1-like and D2-like receptors. The D1-like family comprises the D1 and D5 receptors, whereas D2, D3, and D4 receptors form the D2-like family. 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 (1-9), substantially increasing our knowledge of the dopaminergic system (10, 11).Among DA receptors the most widely and abundantly expressed in the central nervous system are the D1 and D2 receptors, whereas D3, D4, and D5 have lower abundance and a very restricted localization. Mutation of the D1 gene (D1r) in mice resulted in growth retardation, failure to respond to the motor stimulant effects of addictive drugs, and poor learning performance (2,3,(12)(13)(14). Moderate growth retardation was also reported in mice lacking D2 receptors (D2r Ϫ/Ϫ ), which in addition are hypoactive, fail to experience the rewarding properties of morphine, and lose DA autoreceptor function (4, 15, 16).Importantly, neuroanatomical as well as pharmacological studies have pro...