The role of lysophosphatidic acid (LPA) signaling in psychiatric disorders and drug abuse is significant. LPA receptors are widely expressed in the central nervous system, including the lateral habenula (LHb). Recent studies suggest that LHb is involved in a negative emotional state during alcohol withdrawal, which can lead to relapse. The current study examines the role of LHb LPA signaling in the negative affective state associated with alcohol withdrawal. Adult male Long-Evans rats were trained to consume either alcohol or water for eight weeks. At 48 h of withdrawal, alcohol-drinking rats showed anxiety- and depression-like symptoms, along with a significant increase in LPA signaling and related neuronal activation molecules, including autotaxin (ATX, Enpp2), LPA receptor 1/3 (LPA1/3), βCaMKII, and c-Fos. However, there was a decrease in lipid phosphate phosphatase-related protein type 4 (LPPR4) in the LHb. Intra-LHb infusion of the LPA1/3 receptor antagonist ki-16425 or PKC-γ inhibitor Go-6983 reduced the abnormal behaviors and elevated relapse-like ethanol drinking. It also normalized high LPA1/3 receptors and enhanced AMPA GluA1 phosphorylation in Ser831 and GluA1/GluA2 ratio. Conversely, selective activation of LPA1/3 receptors by intra-LHb infusion of 18:1 LPA induced negative affective states and upregulated βCaMKII-AMPA receptor phosphorylation in Naive rats, which were reversed by pretreatment with intra-LHb Go-6983. Our findings suggest that disturbances in LPA signaling contribute to adverse affective disorders during alcohol withdrawal, likely through PKC-γ/βCaMKII-linked glutamate signaling. Targeting LPA may therefore be beneficial for individuals suffering from alcohol use disorders.
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This work is made possible by the National Natural Science Foundation of China (82071496 to Rao Fu), the Young Teacher Foundation of Sun Yat-sen University (59000-18841219 Rao Fu), Natural Science Foundation of Guangdong Province (2021A1515010463 to Rao Fu), the Shenzhen Science and Technology Program (202205303001697 to Rao Fu), the Fellowship of China Postdoctoral Science Foundation (2022M711491 to Ying Tang) and the Fund of Shenzhen Key Laboratory (ZDSYS20220606100803007) .
The authors declare no competing interests.
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Ren, Z., Hou, J., Li, W. et al. LPA1 receptors in the lateral habenula regulate negative affective states associated with alcohol withdrawal. Neuropsychopharmacol. 48, 1567–1578 (2023). https://doi.org/10.1038/s41386-023-01582-8