Up‐regulation of `peripheral‐type' benzodiazepine receptors in the globus pallidus in manganese neurotoxicity

Increasing evidence suggests that astrocytes play a major role in damage to the nervous system in manganese neurotoxicity (MN). Astrocytes accumulate manganese and sequester the metal in mitochondria where it inhibits oxidative phosphorylation. Chronic exposure to manganese leads to selective neuronal loss in basal ganglia structures such as the globus pallidus together with characteristic astrocytic changes known as Alzheimer type II astrocytosis. In previous reports we have demonstrated that treatment of these cells with manganese leads to increased binding site densities of the ‘peripheral‐type’ benzodiazepine receptor (PTBR) complex (Hazell et al . 1999; Neurosci. Lett . 271 , 5–8), found predominantly in astrocytes and an important source of neurosteroid production. In the present study, we have examined the effects of manganese treatment in a subacute rat model of manganese neurotoxicity. Male Sprague–Dawley rats (200 g) were administered manganese (II) chloride (50 mg/kg, i.p. in 0.2 mL saline) daily for 1 and 4 days while control animals were injected with carrier only. Using neutron activation analysis, levels of manganese in the globus pallidus were found to be increased by 81% after 24 h of treatment but were elevated by 551% compared to controls after 4 days. Manganese treatment also led to a 110% increase in levels of the 18 kDa isoquinoline carboxamide‐binding protein, a major constituent of the PTBR, after 4 days but with no change in protein expression at 1 day by immunoblotting, consistent with the neutron activation findings. These results indicate that PTBRs and possibly neurosteroids are an early response to manganese exposure and may play a major role in the pathophysiology of MN.