Nicergoline improves the depressive behavior of vascular depression in rats by regulating monoamine neurotransmitter receptors expression in hippocampal CA1 region and serum apolipoprotein E4 level

Abstract

Objective To investigate the effects of nicergoline on expressions of 5-hydroxytryptamine 1A receptor (5-HT1AR), D2 dopamine receptor (D2DR), α2A adrenaline receptor (α2AAR) in the hippocampal CA1 region and the serum level of apolipoprotein E4 (ApoE4) in a rat model of vascular depression (VD). Methods Forty-eight male Sprague-Dawley rats were randomly allocated into a normal control group, a model group, fluoxetine group, a low-dose nicergoline group, a medium-dose nicergoline group, and a nicergoline high-dose group (n=8 in each group). A rat model of VD was induced by the ligation of bilateral common carotid arteries combined with chronic unpredictable mild stress (CUMS) plus single housing. The rats did not conduct CUMS or single housing in the normal control group, and the rats in the model group conducted CUMS and single housing. The rats in the fluoxetine group were given fluoxetine 1.3 mg/(kg·d) for gastric lavage for 3 weeks at the beginning of CUMS and single housing. The rats in the low-, medium-and high-dose nicergoline groups were given nicergoline 0.9, 1.9 and 3.8 mg/(kg·d), respectively for gastric lavage for 3 weeks at the beginning of CUMS and single housing. The normal control group and the model group were given equal volume of distilled water for gastric lavage, once a day for 3 weeks. Depression-like behavior was evaluated using sucrose solution consumption and open-field test. Immunohistochemical staining and Western blot were used to detect the expressions of 5-HT1AR, D2DR, and α2AAR in the hippocampal CA1 region. Enzyme linked immunosorbent assay was used to detect serum ApoE4 level. Results Before CUMS, the scores of horizontal and vertical movement and sucrose solution consumption in the model group, the fluoxetine group and each nicergoline group were decreased significantly compared with the normal control group (all P<0.01); while at 21 days after CUMS, those in the fluoxetine group and the nicergoline medium- and high-dose groups were significantly higher than those in the model group (all P<0.05). There were no significant differences between the fluoxetine group and each nicergoline group. The expression levels of 5-HT1AR, D2DR, α2AAR, and the serum ApoE4 in the model group, the fluoxetine group, and each nicergoline group were significantly higher than those in the normal control group. Those of the fluoxetine group and the nicergoline medium- and high-dose groups were significantly lower than the model group (all P<0.01), while there were no significant differences between the fluoxetine group and each nicergoline group. Conclusions Nicergoline can improve the depression-like behavior in VD rats. Its mechanism may be associated with the downregulation of 5-HT1AR, D2DR, α2AAR expressions and serum ApoE4 level. Key words: Brain Ischemia; Depression; Nicergoline; Biogenic Monoamines; Receptor, Serotonin, 5-HT1A; Receptors, Dopamine D2; Receptors, Adrenergic, α-2; Apolipoprotein E4; Rats