The histidine triad nucleotide binding 1 protein is involved in nicotine reward and physical nicotine withdrawal in mice

Smoking rates among individuals with schizophrenia are significantly higher than the general population. One possible explanation for this comorbidity is that there are shared genes and biological pathways between smoking and schizophrenia. The histidine triad nucleotide binding protein 1 (HINT1) is a potential candidate, as genetic association and expression studies implicate the gene in both schizophrenia and nicotine dependence; however, the behavioral role of HINT1 in nicotine dependence is unknown. Thus, the goal of the current study was to determine the behavioral role of HINT1 in nicotine dependence. We tested male HINT1 wild-type (+/+) and knockout (−/−) mice in the nicotine conditioned place preference (CPP) test of reward, a nicotine withdrawal model assessing both physical and affective signs, and the nicotine withdrawal conditioned place aversion (CPA) test. HINT1 −/− mice failed to develop a significant nicotine CPP and physical withdrawal signs (hyperalgesia and somatic signs) were attenuated in HINT1 −/− mice. Conversely, HINT1 −/− mice developed a significant nicotine withdrawal CPA similar to their ++ counterparts. Overall, our data support a role for the HINT1 gene in mediating behaviors associated with nicotine reward and physical nicotine withdrawal, and provide insight into the role of HINT1 in nicotine dependence-like behaviors.