Association of the histidine-triad nucleotide-binding protein-1 (HINT1) gene variants with nicotine dependence

Abstract

The histidine triad nucleotide-binding protein-1 gene (HINT1) is implicated in schizophrenia and in the behavioral effects of morphine and amphetamine. Because nicotine dependence (ND) is highly comorbid with schizophrenia and other substance abuse, we examined the association of HINT1 with ND. Association analyses from two independent samples show that HINT1 gene variants are associated with ND phenotypes. Furthermore, human postmortem mRNA expression shows that smoking status and genotype influence HINT1 expression in the brain. In animal studies, western blot analyses show an increase of HINT1 protein level in the mouse nucleus accumbens (NAc) after chronic nicotine exposure. This increase was reduced after treatment with the nicotinic-receptor antagonist mecamylamine, and 24 and 72 h after cessation of nicotine treatment. These results indicate a genetic association between HINT1 variants and ND, and indicate that nicotine-induced modulation of HINT1 level may be involved in mechanisms of excess smoking.

Figure 1

HINT1 protein levels are increased in the NAc after chronic nicotine exposure and reduced after mecamylamine treatment and nicotine withdrawal. Mice were chronically infused with nicotine (36mgkg⁻¹day⁻¹) for 14 days. Brain sections were dissected on the morning of day 15, 30 min after saline or mecamylamine (2mgkg⁻¹, s.c.) injection. Chronic nicotine induced a significant increase in the HINT1 level in the NAc (a, b). (a) The chronic nicotine-induced increase in the HINT1 level in the NAc was reduced after mecamylamine treatment. (b) The chronic nicotine-induced increase in the HINT1 level in the NAc returned to baseline levels 24 and 72 h after nicotine withdrawal. The y-axis of the graph represents the percent change from baseline (saline). Each point represents the mean ± s.e.m. of four mice per group. Results were pooled from three separate experiments for each brain section. * denotes P<0.05 versus saline baseline and + denotes P<0.05 versus the chronic nicotine and saline groups. α-tbn, α-tubulin; HINT1, histidine-triad nucleotide-binding protein-1; NAc, nucleus accumbens; nic, nicotine; Sal, saline; s.c., subcutaneous.