Compensatory responses to nigrostriatal bundle injury. Studies with 6-hydroxydopamine in an animal model of parkinsonism.

Intracerebral injections of the neurotoxin 6-hydroxydopamine (6-HDA) can produce selective, near-total destruction of the dopamine (DA)-containing neurons of the nigrostriatal bundle. The dysfunctions in animals with these lesions show many parallels with those present in Parkinsonian patients. Among these are the extensive loss of DA neurons in the basal ganglia, neurological impairments including akinesia, paradoxical kinesia in response to activating conditions, and improved sensory-motor function after the administration of DOPA. Moreover, as with patients with preclinical Parkinsonism, 6-HDA-treated rats with less extensive lesions show few or no behavioral dysfunctions, but are unusually sensitive to the akinesia-inducing effects of stress and dopaminergic antagonists. In this review, we summarize the behavioral effects of 6-HDA-induced depletion of striatal DA in the rat and then focus on the compensatory changes that may underlie the preclinical stage of the disorder. These compensations appear to include an increase in the number of active DA neurons, an increase in the release of DA per impulse from residual terminals, and a decrease in the amount of DA inactivated by high affinity uptake. Collectively, these alterations permit a few residual DA neurons to maintain a normal level of control over cellular activity in the striatum.