Chronic exposure to inorganic mercury alters stress responses in male prairie voles (Microtus ochrogaster).

Male, but not female, prairie voles that experience chronic exposure to inorganic mercury display aberrant social behavior - avoiding unfamiliar conspecifics rather than approaching them. The mechanisms that underlie such behavioral changes are unknown, but likely involve the hypothalamus-pituitary-adrenal (HPA) axis. We tested this hypothesis by providing voles of both sexes with mercury chloride in their drinking water for ten weeks and then staging same-sex dyadic encounters after which plasma was assayed for corticosterone as an index of HPA activity. Consistent with sex-specific behavioral responses previously reported, mercury-treated males had lower plasma corticosterone after social encounters than did similarly-treated females or males that consumed normal drinking water. The results suggest that mercury-treated males may be less inclined toward social engagement with conspecifics due to reduced HPA activity.

The ß3 subunit of the nicotinic acetylcholine receptor: Modulation of gene expression and nicotine consumption.

Genetic factors explain approximately half of the variance in smoking behaviors, but the molecular mechanism by which genetic variation influences behavior is poorly understood. SNPs in the putative promoter region of CHRNB3, the gene that encodes the ß3 subunit of the nicotinic acetylcholine receptor (nAChR), have been repeatedly associated with nicotine behaviors. In this work we sought to identify putative function of three SNPs in the promoter region of CHRNB3 on in vitro gene expression. Additionally, we used ß3 null mutant mice as a model of reduced gene expression to assess the effects on nicotine behaviors. The effect of rs13277254, rs6474413, and rs4950 on reporter gene expression was examined using a luciferase reporter assay. A major and minor parent haplotype served as the background on which alleles at the three SNPs were flipped onto different backgrounds (e.g. minor allele on major haplotype background). Constructs were tested in three human cell lines: BE(2)-C, SH-SY5Y and HEK293T. In all cell types the major haplotype led to greater reporter gene expression compared to the minor haplotype, and results indicate that this effect is driven by rs6474413. Moreover, mice lacking the ß3 subunit showed reduced voluntary nicotine consumption compared that of wildtype animals. These data provide evidence that the protective genetic variant at rs6474413 identified in human genetic studies reduces gene expression and that decreased ß3 gene expression in mice reduces nicotine intake. This work contributes to our understanding of the molecular mechanisms that contribute to the human genetic associations of tobacco behaviors.