LOCOMOTOR-ACTIVITY IN D2 DOPAMINE RECEPTOR-DEFICIENT MICE IS DETERMINED BY GENE DOSAGE, GENETIC BACKGROUND, AND DEVELOPMENTAL ADAPTATIONS

Locomotor activity is a polygenic trait that varies widely among inbre d strains of mice (Flint et at., 1995). To characterize the role of D2 dopamine receptors in locomotion, we generated F-2 hybrid (129/Sv x C 57BV6) D2 dopamine receptor (D2R)deficient mice by gene targeting and investigated the contribution of genetic background to open-field acti vity and rotarod performance. Horizontal activity of D2R-/- mice was a pproximately half that of drug-naive, strain-matched controls but was significantly greater than haloperidol-treated controls, which were ma rkedly hypokinetic. Wild-type 129/SvEv and C57BL/6 mice with functiona l D2 receptors had greater interstrain differences in spontaneous acti vity than those among the F-2 hybrid mutants. Incipient congenic strai ns of D2R-deficient mice demonstrated an orderly gene dosage reduction in locomotion superimposed on both extremes of parental background lo comotor activity. In contrast, F-2 hybrid D2R-/- mice had impaired mot or coordination on the rotarod that was corrected in the congenic C57B /6 background. Wild-type 129/SvEv mice had the poorest rotarod ability of all groups tested, suggesting that linked substrain 129 alleles, n ot the absence of D2 receptors per se, were largely responsible for th e reduced function of the F-2 hybrid D2R-/- and D2R+/- mice. Neurochem ical and pharmacological studies revealed unexpectedly normal tissue s triatal monoamine levels and no evidence for supersensitive D1, D3, or D4 dopamine receptors in the D2R-/- mice. However, after acute monoam ine depletion, akinetic D2R+/- mice had a significantly greater synerg istic restoration of locomotion in response to SKF38393 and quinpirole compared with any group of D2R+/+ controls. We conclude that D2R-defi cient mice are not a model of Parkinson's disease, Our studies highlig ht the interaction of multiple genetic factors in the analysis of comp lex behaviors in gene knock-out mice.