ALTERED STRIATAL FUNCTION IN A MUTANT MOUSE LACKING D-1A DOPAMINE-RECEPTORS

Of the five known dopamine receptors, D-1A and D-2 represent the major subtypes expressed in the striatum of the adult brain. Within the striatum, these two subtypes are differentially distributed in the two main neuronal populations that provide direct and indirect pathways between the striatum and the output nuclei of the basal ganglia. Movement disorders, including Parkinson disease and various dystonias, are thought to result from imbalanced activity in these pathways. Dopamine regulates movement through its differential effects on D-1A receptors expressed by direct output neurons and D-2 receptors expressed by indirect output neurons. To further examine the interaction of D-1A and D-2 neuronal pathways in the striatum, we used homologous recombination to generate mutant mice lacking functional D-1A receptors (D-1A-/-) D-1a-/- mutants are growth retarded and die shortly after weaning age unless their diet is supplemented with hydrated food. With such treatment the mice gain weight and survive to adulthood. Neurologically, D-1A-/- mice exhibit normal coordination and locomotion, although they display a significant decrease in rearing behavior. Examination of the striatum revealed changes associated with the altered phenotype of these mutants. D-1A receptor binding was absent in striatal sections from D-1A-/- mice. Striatal neurons normally expressing functional D-1A receptors are formed and persist in adult homozygous mutants. Moreover, substance P mRNA, which is colocalized specifically in striatal neurons with D-1A receptors, is expressed at a reduced level. In contrast, levels of enkephalin mRNA, which is expressed in striatal neurons with D-2 receptors, are unaffected. These findings show that D-1A-/- mice exhibit selective functional alterations in the striatal neurons giving rise to the direct striatal output pathway.