Chronic manganese exposure disrupts dopamine biosynthesis and amphetamine response in a mouse model of altered dopamine transport

The capacity for excess manganese to alter dopaminergic systems resulting in neurobehavioral deficits is clear, yet far less is known the impact of chronic, lower, sub-toxic manganese exposures. Manganese exposure may affect dopamine synthesis and metabolism, and as such impact drug efficacy. These may also occur to a greater extent in populations with genetic variants that render them more vulnerable to intellectual developmental disabilities. DAT^T356M/+ mice were used as a model of altered dopamine transport via an autism-linked single nuclear polymorphism in the dopamine transporter. Following 12 weeks feeding of manganese (2400 ppm) mild changes in spontaneous and repetitive behaviors such as climbing and rearing were induced by both genotype and manganese although the patterns differed according to age and sex. Female mice also exhibited a decrease in activity in response to amphetamine compared to control-fed mice (70 ppm) littermates independent of the decreased response observed in DAT^T356M/+ mice. Males showed a more robust effect of genotype suppression of the amphetamine response but no further effect of manganese. Behavioral changes occurred in the absence of significant impact of dietary manganese on body weight. Manganese exposure was associated with altered gene expression in nucleus accumbens relating to metal transport (Slc11a2, Slc39a8, Slc39a14, Slc30a10) and dopamine regulation (TH, Slc6a3) that did not show clear differences according to sex. Changes at the RNA level were not replicated in protein expression changes measured in the striatum. There were no changes in levels of dopamine or metabolites in the cortex according to genotype or manganese, although manganese exposure was associated with decreased norepinephrine and increased serotonin. SNCA has a regulatory role in dopamine neurotransmission and snca gene expression was significantly down regulated by both DAT^T356M/+ genotype and manganese diets. The altered dopamine changes and response to amphetamine between sexes in presence of Mn highlights the potential role of sub-toxic exposures to heavy metals in moderating behavioral profiles and drug responses. The lack of consistent differences according to sex, genotype and exposure across all outcomes also suggests the complexity of the specific pathways and mechanisms driving the behavioral differences.