Effects of Hint1 deficiency on emotional‐like behaviors in mice under chronic immobilization stress

Abstract Background Histidine triad nucleotide‐binding protein 1 ( HINT 1) is regarded as a haplo‐insufficient tumor suppressor and is closely associated with diverse neuropsychiatric diseases. Moreover, HINT 1 is related to gender‐specific acute behavior changes in schizophrenia and in response to nicotine. Stress has a range of molecular effects in emotional disorders, which can cause a reduction in brain‐derived neurotrophic factor ( BDNF ) expression in the hippocampus, resulting in hippocampal atrophy and neuronal cell loss. Methods This study examined the role of HINT 1 deficiency in anxiety‐related and depression‐like behaviors and BDNF expression in the hippocampus under chronic immobilization stress, and investigated whether the sex‐specific and haplo‐insufficient effects exist in emotional‐like behaviors under the same condition. Results In a battery of behavior tests, the results of the control group, not exposed to stress, showed that knockout ( KO ) and heterozygosity ( HT ) of Hint1 had anxiolytic‐like and antidepression‐like effects on the male and female mice. However, both male and female Hint1 ‐ KO mice showed elevated anxiety‐related and antidepression‐like behavior under chronic immobilization stress; moreover, both male and female Hint1 ‐ HT mice displayed elevated anxiety‐related behavior and increased depression‐like behavior under chronic immobilization stress. There were no significant differences in general locomotor activity between Hint1 ‐ KO and ‐ HT mice and their wild‐type ( WT ) littermates. Hint1 ‐ KO mice under basal and chronic immobilization stress conditions expressed more BDNF in the hippocampus than did Hint1 ‐ HT and WT mice; overall, there were no significant sex differences in emotional‐like behaviors of Hint1 ‐ KO and ‐ HT mice. Additionally, Hint1‐ HT mice showed haplo‐insufficient effects on emotional‐like behaviors under basic conditions, rather than under chronic immobilization stress. Conclusions Both male and female HINT 1 KO and HT mice had a trend of anxiolytic‐like behavior and antidepression‐like behavior at control group. However, both male and female HINT 1 KO mice showed elevated anxiety‐related and antidepression‐like behavior under chronic immobilization stress; moreover, both male and female HINT 1 HT mice displayed elevated anxiety‐related behavior and increased depression‐like behavior under chronic immobilization stress.