Dopaminergic brain system in the quaking mutant mouse

Abstract

Quaking mice ( qk qk ), autosomal recessive mutants with central nervous system dysmyelinization, characterized behaviorally by abnormal locomotion and tremor, are found to have altered brain dopaminergic system parameters, in comparison with phenotypically normal heterozygous littermates. Dopamine metabolism is enhanced in structures of both nigrostriatal and mesolimbic systems, as revealed by increased metabolites content (that of homovanillic acid in striatum and concentration of 3,4-dihydroxyphenylacetic acid in nucleus accumbens with tuberculum olfactorium) along with unchanged neurotransmitter levels in qk qk mice. D 1 and D 2 receptor analysis via radioligand binding using [ 3H]-SCH 23390 and [ 3H]-spiperone, correspondingly, showed an increase of D 2 receptor density with decreased affinity to D 2 ligand in striatum of mutants: both B max and K d were markedly higher. D 1 and D 2 receptor sensitivity in the quaking mouse was also altered. Stimulation of D 1 receptors by a highly specific agonist SKF 38393 (2.5 and 5 mg/kg) decreased locomotor activity only in mutants, but not in controls. In contrast, qk qk were less sensitive than phenotypically normal qk/+ mice to a selective D 2 dopamine receptor agonist, LY 171555 (quinpirole, 1 and 2.5 mg/kg). The alterations found in the brain dopaminergic system of qk qk mice may be responsible for the behavioral expression of this neurologic mutation.