Role of genotype in brain dopamine metabolism and dopamine-dependent behavior of mice

In mice of eight inbred strains-BALB/c, AKR/J, DBA/2, CBA, C57B1/6, DD, CC57Br, and C3H/He-brain dopamine and its metabolites, 3,4-dihydroxyphenylacetic acid (DOPAC) and homovanillic acid (HVA), in striatum and nucleus accumbens with tuberculum olfactorium, the structures of two main dopaminergic systems-nigrostriatal and mesolimbic-were determined. In both dopaminergic regions, no strain effect on either dopamine or DOPAC levels was found, while for HVA content a highly significant hereditary determination was shown. Influences of selective D₁ and D₂ dopamine receptor agonists-SK&F 38393 and quinpirole, respectively-as well as that of a mixed D₁ D₂ agonist, apomorphine, on general locomotor activity and stereotypic climbing were studied. By that, marked genotypic differences in dopamine-dependent behavior and dopamine receptor sensitivity were observed. Although both SK&F 38393 (5 mg/kg) and apomorphine (0.25 mg/kg) decreased locomotion, the effect being genotype dependent, in all strains of mice quinpirole (2.5 mg/kg) proved more potent in locomotor inhibition. SK&F 38393 (10 mg/kg) induced climbing, but 2.5 mg/kg apomorphine in most strains was much more effective. At the same time, quinpirole (up to 8 mg/kg) failed to induce this behavior. This suggests the crucial role of D₁ receptors in the generation of climbing, attracting, at the same time, attention to the importance of D₁ D₂ interaction. The observed drastic interstrain differences in dopamine receptor sensitivity demonstrate the essential role of genotype in the effects of dopaminergic drugs.