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The Journal of Neuroscience, May 1, 1998, 18(9):3470-3479

Locomotor Activity in D2 Dopamine Receptor-Deficient Mice Is Determined by Gene Dosage, Genetic Background, and Developmental Adaptations

Michele A. Kelly^{1, 2}, Marcelo Rubinstein¹, Tamara J. Phillips^{3, 5}, Christina N. Lessov³, Sue Burkhart-Kasch³, Ge Zhang⁴, James R. Bunzow⁴, Yuan Fang⁴, Gregory A. Gerhardt⁶, David K. Grandy⁴, and Malcolm J. Low¹

Oregon Health Sciences University, ¹ Vollum Institute, Departments of ² Cell and Developmental Biology, ³ Behavioral Neuroscience, and ⁴  Physiology and Pharmacology, Portland, Oregon 97201, ⁵ Veterans Affairs Medical Center, Portland, Oregon 97201, and ⁶ Department of Psychiatry, University of Colorado Health Sciences Center, Denver, Colorado 80262

Locomotor activity is a polygenic trait that varies widely among inbred strains of mice (). To characterize the role of D2 dopamine receptors in locomotion, we generated F₂ hybrid (129/Sv × C57BL/6) D2 dopamine receptor (D2R)-deficient mice by gene targeting and investigated the contribution of genetic background to open-field activity and rotarod performance. Horizontal activity of D2R/ mice was approximately half that of drug-naive, strain-matched controls but was significantly greater than haloperidol-treated controls, which were markedly hypokinetic. Wild-type 129/SvEv and C57BL/6 mice with functional D2 receptors had greater interstrain differences in spontaneous activity than those among the F₂ hybrid mutants. Incipient congenic strains of D2R-deficient mice demonstrated an orderly gene dosage reduction in locomotion superimposed on both extremes of parental background locomotor activity. In contrast, F₂ hybrid D2R/ mice had impaired motor coordination on the rotarod that was corrected in the congenic C57BL/6 background. Wild-type 129/SvEv mice had the poorest rotarod ability of all groups tested, suggesting that linked substrain 129 alleles, not the absence of D2 receptors per se, were largely responsible for the reduced function of the F₂ hybrid D2R/ and D2R+/ mice. Neurochemical and pharmacological studies revealed unexpectedly normal tissue striatal monoamine levels and no evidence for supersensitive D1, D3, or D4 dopamine receptors in the D2R/ mice. However, after acute monoamine depletion, akinetic D2R+/ mice had a significantly greater synergistic restoration of locomotion in response to SKF38393 and quinpirole compared with any group of D2R+/+ controls. We conclude that D2R-deficient mice are not a model of Parkinson's disease. Our studies highlight the interaction of multiple genetic factors in the analysis of complex behaviors in gene knock-out mice.

Key words: D2 dopamine receptor; genetics; locomotor activity; C57BL/6 mice; 129/SvEv mice; dopamine; rotarod; gene knock-out mice

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Copyright © 1998 Society for Neuroscience  0270-6474/98/1893470-10$05.00/0

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