Persistent effects of manganese on effortful responding and their relationship to manganese accumulation in the primate globus pallidus.

Manganese produces signs and symptoms that suggest involvement of the basal ganglia, especially the globus pallidus and substantia nigra. Overt neurological signs have been reported in primates exposed to high levels of manganese (over 100 mg/kg) but little is known about the effects of lower doses. To examine these issues, three cebus monkeys were trained to operate a response device with their arms and legs by executing a rowing-like movement against a 3.9- to 4.1-kg spring through an arc length of 10 cm under a multiple fixed-ratio fixed-interval schedule of reinforcement. Over the course of 450 days, these monkeys were administered acute doses of 5 or 10 mg/kg iv of manganese chloride using a multiple baseline experimental design. Doses as low as 5 mg/kg provoked a large increase in the number of incomplete responses. The onset of manganese's effect appeared within days of exposure and developed over the course of several weeks. Its magnitude declined over the course of months, but after a cumulative dose of 10 to 40 mg/kg it did not return to baseline. Action tremor appeared at cumulative doses greater than 40 mg/kg and dystonia was never observed at the cumulative doses examined. Behavioral microanalysis revealed that manganese's effects initially appeared as increased variability of interresponse times and response duration. Later, the response pattern during the fixed ratio component shifted to one of progressively increasing durations through the course of the ratio. Magnetic resonance imaging revealed that the behavioral effects of manganese corresponded to an apparent increase in the manganese content of the globus pallidus and substantia nigra.