Pharmacological analysis of extracellular dopamine and metabolites in the striatum of conscious AS/AGU rats, mutants with locomotor disorder

The as/agu rat is a spontaneously occurring mutation which exhibits locomot or abnormalities, reduced tyrosine hydroxylase levels in the substantia nig ra and lower extracellular levels of dopamine. The animal could represent a model of some human locomotor disorders. High-potassium medium evoked a 46 0% rise of dopamine levels in control rats but double this in mutants. Amph etamine increased extracellular dopamine by 710% in controls and 1480% in m utants. Clorgyline produced a small increase of dopamine levels in controls but an 1170% increase in mutants. The uptake inhibitor nomifensine increas ed dopamine levels by 910% in controls but only 270% in mutants. After trea tment with benserazide plus L-DOPA, an acute injection of L-DOPA evoked a r elease of dopamine which was twice as large in the as/agu rats compared wit h 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 fr om 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 def ective regulation of dopamine release from striatal terminals. (C) 2000 IBR O. Published by Elsevier Science Ltd. All rights reserved.