The AS/AGU rat: a spontaneous model of disruption and degeneration in the nigrostriatal dopaminergic system

The AS/AGU rat provides an alternative to experimentally produced laborator y models of basal ganglia disorders. This mutant is characterised by distur bances of movement including clumsy gait, whole body tremor, rigidity and d ifficulty in initiating movement. From an early age, there is a profound de pletion of extracellular dopamine in the dorsal caudate-putamen as measured via in vivo microdialysis; levels are only 10-20 % of those found in the p arent Albino Swiss (AS) strain. Subsequently a depletion of whole tissue do pamine levels occurs and, later still, loss of dopaminergic cells in the su bstantia nigra pars compacta. The dysfunction in movement and the nigrostri atal dopaminergic system are clearly linked, since movement can be ameliora ted by L-DOPA administration. Furthermore, there are depletions in glucose utilisation in several regions of the basal ganglia circuitry, including th e substantia nigra pars compacta, the subthalamic nucleus and the ventrolat eral thalamus. The AS/AGU rat represents a unique opportunity to investigat e the intrinsic factors controlling the integrity of dopaminergic systems a nd the recent successful positional cloning of the agu gene will allow the molecular mechanisms underlying this interesting phenotype to be analysed.