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LPA1 receptors in the lateral habenula regulate negative affective states associated with alcohol withdrawal

Neuropsychopharmacology volume 48, pages 1567–1578 (2023)Cite this article

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Abstract

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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Fig. 1: Effects of chronic alcohol exposure and withdrawal on LPA-related gene and protein expression in the LHb.
Fig. 2: Inhibiting LHb LPA1/3 receptors mitigates anxiety- and depression-like behaviors downregulated CaMKII-AMPAR cascades in Post-EtOH rats.
Fig. 3: Activating LHb LPA1/3 receptors induces anxiety- and depression-like behaviors and upregulates CaMKII-AMPAR cascades in Naïve rats.
Fig. 4: Blocking LHb PKC-γ downregulates LHb βCaMKII-AMPA signaling and alleviates negative affective states of Post-EtOH rats.
Fig. 5: Intra-LHb infusion of ki-16425 or Go-6983 reduces alcohol consumption and c-Fos expression in Post-EtOH rats.

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Funding

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) .

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  1. Ying Tang

    Present address: Basic and Clinical Medicine Teaching Laboratory, School of Medicine, Sun Yat-sen University, Shenzhen, Guangdong, 518100, China

  2. These authors contributed equally: Zhiheng Ren, Jiawei Hou.

Authors and Affiliations

  1. Department of Anatomy, School of Medicine, Shenzhen Campus of Sun Yat-Sen University, Sun Yat-sen University, Shenzhen, Guangdong, 518106, China

    Zhiheng Ren, Jiawei Hou, Wenfu Li, Ruxuan Ding, Songlin Liu, Yixin Fu, Yunlin Mai, Li-Hua Zhou & Rao Fu

  2. Department of Biology, School of Life Science, Southern University of Science and Technology, Shenzhen, Guangdong, 518055, China

    Ying Tang

  3. Basic and Clinical Medicine Teaching Laboratory, School of Medicine, Sun Yat-sen University, Shenzhen, Guangdong, 518100, China

    Molin Wang

  4. Department of Basic Medical Sciences, Yunkang School of Medicine and Health, Nanfang College, Guangzhou, Guangdong, 510970, China

    Jianxun Xia

  5. Department of Anesthesiology, Pharmacology, Physiology & Neuroscience, Rutgers, The State University of New Jersey, New Jersey Medical School, Newark, NJ, 07103, USA

    Wanhong Zuo & Jiang-Hong Ye

  6. Shenzhen Key Laboratory for Systems Medicine in Inflammatory Diseases, School of Medicine, Shenzhen Campus of Sun Yat-Sen University, Sun Yat-Sen University, Shenzhen, 518106, China

    Rao Fu

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Contributions

ZHR, JWH and WFL established the AUD animal models; ZHR and WFL performed the animal stereotaxic surgery; ZHR, YT, YXF, YLM, and SLL performed behavioral tests; ZHR, JWH, MLW and RXD conducted molecular biology and histology experiments; ZHR analyze data and drafted the manuscript; JXX, WHZ, YT and JHY contributed to data interpretation and editing of the manuscript. LHZ is the supervisor of ZHR and JWH. RF contributed to experimental design and conception, data interpretation, editing, and final approval of the manuscript.

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Correspondence to Jiang-Hong Ye or Rao Fu.

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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

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  • DOI: https://doi.org/10.1038/s41386-023-01582-8

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