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

BACKGROUND Histidine triad nucleotide-binding protein 1 (HINT1) is regarded as a haplo-insufficient tumor suppressor and is closely associated with diverse neuropsychiatric diseases. Moreover, HINT1 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 HINT1 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 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.