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\begin{document}

\title{Bile duct ligation increased dopamine levels in the cerebral cortex of
rats partly due to induction of tyrosine hydroxylase}



\author[1]{Weimin kong}%
\author[1]{Xueying Sun}%
\author[1]{Siyu Yu}%
\author[1]{Peihua Liu}%
\author[1]{Xiaoke zheng}%
\author[1]{Jiaxin Zhang}%
\author[1]{Liang Zhu}%
\author[1]{Tianxin Jiang}%
\author[1]{Mengmeng Jin}%
\author[1]{Jinghui Gao}%
\author[1]{XiaoDong Liu}%
\author[1]{Li Liu}%
\affil[1]{China Pharmaceutical University}%


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  \date{March 14, 2025}


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\begin{abstract}
Background and Purpose Liver failure is often associated with
psychiatric alterations, partly resulting from the increased dopamine
levels in brain. We aimed to investigate relationship between increased
dopamine levels and mental abnormalities using bile duct ligation (BDL)
rats and document mechanism that liver failure increased dopamine levels
in SH-SY5Y cells. Experimental Approach Psychiatric alterations were
operated following 14-day BDL. Dopamine and its metabolite levels in
cortex, expressions of enzymes and transporters related to dopamine
metabolism and transport in cortex and hippocampus were measured.
SH-SY5Y cells were used to investigate whether NH4Cl, bile acids and
bilirubin affected expression of tyrosine hydroxylase (TH) or not. TH
expression in SH-SY5Y cells co-incubated with bilirubin and signal
pathway inhibitors was measured. Key Results Open-field test results
showed a remarkable increase in exploratory behavior following BDL. BDL
increased dopamine levels and expression of TH protein in cortex. MAO-A
and Mb-COMT slightly but significantly decreased. Data from SH-SY5Y
cells showed that increased bilirubin levels was a factor in inducing TH
expression. Both inhibitor of NF-\selectlanguage{greek}κ\selectlanguage{english}B pathway BAY117082 and silencing p65
remarkably reversed bilirubin-induced upregulation of TH protein. NF-\selectlanguage{greek}κ\selectlanguage{english}B
activator TNF-\selectlanguage{greek}α \selectlanguage{english}increased expression of TH protein. Roles of bilirubin
in TH expression and increases in dopamine levels were documented using
hyperbilirubinemia rats. Significant increases in dopamine levels,
expressions of TH, p65 and p-p65 protein were observed in
hyperbilirubinemia rats. Conclusion and Implications BDL significantly
increased dopamine levels in rat cortex partly due to bilirubin-mediated
TH induction. Increased bilirubin induced TH expression via activating
NF-\selectlanguage{greek}κ\selectlanguage{english}B signaling pathway.%
\end{abstract}%



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