ABSTRACT
The as/agu rat is a spontaneously occurring mutation which exhibits locomotor abnormalities, reduced tyrosine hydroxylase levels in the substantia nigra and lower extracellular levels of dopamine. The animal could represent a model of some human locomotor disorders. High-potassium medium evoked a 460% rise of dopamine levels in control rats but double this in mutants. Amphetamine increased extracellular dopamine by 710% in controls and 1480% in mutants. Clorgyline produced a small increase of dopamine levels in controls but an 1170% increase in mutants. The uptake inhibitor nomifensine increased dopamine levels by 910% in controls but only 270% in mutants. After treatment with benserazide plus L-DOPA, an acute injection of L-DOPA evoked a release of dopamine which was twice as large in the as/agu rats compared with controls. The results show reduced extracellular dopamine in as/agu rats when the locomotor disorder is apparent, but there has been little loss of tyrosine hydroxylase. The responses to drugs are qualitatively different from those obtained using 6-hydroxydopamine.Overall, the effects of compounds affecting aminergic neurons suggest that one possible mechanism for the neuronal abnormality in as/agu rats is a defective regulation of dopamine release from striatal terminals.
Subject(s)
Corpus Striatum/metabolism , Dopamine/metabolism , Extracellular Space/metabolism , Movement Disorders/genetics , Movement Disorders/metabolism , Amphetamine/pharmacology , Animals , Clorgyline/pharmacology , Corpus Striatum/drug effects , Dopamine Agents/pharmacology , Dopamine Uptake Inhibitors/pharmacology , Levodopa/pharmacology , Male , Mice , Mice, Mutant Strains/genetics , Monoamine Oxidase Inhibitors/pharmacology , Nomifensine/pharmacology , Potassium/pharmacology , Reference ValuesABSTRACT
The AS/AGU rat is a mutant derived from the Albino Swiss (AS) strain. It is characterized by an ungainly, staggering gait, hind limb rigidity, whole body tremor and, in older animals, difficulty in initiating movement. As and AS/AGU males aged three, six and nine months (n=6 per group) were used to estimate the levels of dopamine and its metabolites in the extracellular fluid of the caudate-putamen. The results indicate a profound loss of dopamine in the extracellular fluid at all age points examined, together with an increase in the concentration of the metabolite 3,4-dihydroxyphenylacetic acid. It is suggested that these changes reflect a defect of dopaminergic neuron function which may underlie the motor disorder seen in these animals.
