Acute behavioral effects of nicotine in male and female HINT1 knockout mice

HINT1 is associated with acute nicotine behaviors and a general anxiety phenotype. These associations are sex specific. Human genetic association and brain expression studies, and mouse behavioral and molecular studies implicate a role for the histidine triad nucleotide‐binding protein 1 (HINT1) in schizophrenia, bipolar disorder, depression and anxiety. The high comorbidity between smoking and psychiatric disorders, schizophrenia in particular, is well established. Associations with schizophrenia and HINT1 are also sex specific, with effects more predominant in males; however, it is unknown if sex differences associated with the gene extend to other phenotypes. Thus, in this study, using a battery of behavioral tests, we elucidated the role of HINT1 in acute nicotine‐mediated behaviors using male and female HINT1 wild‐type (+/+) and knockout (−/−) mice. The results show that male HINT1 −/− mice were less sensitive to acute nicotine‐induced antinociception in the tail‐flick, but not hot‐plate test. At low nicotine doses, male and female HINT1 −/− mice were less sensitive to nicotine‐induced hypomotility, although the effect was more pronounced in females. Baseline differences in locomotor activity observed in male HINT1 +/+ and −/− mice were absent in females. Nicotine did not produce an anxiolytic effect in male HINT1 −/− mice, but rather an anxiogenic response. Diazepam also failed to induce an anxiolytic response in these mice, suggesting a general anxiety phenotype not specific to nicotine. Differences in anxiety‐like behavior were not observed in female mice. These results further support a role for HINT1 in nicotine‐mediated behaviors and suggest that alterations in the gene may have differential effects on phenotype in males and females.