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Glutamatergic neurons in ventral pallidum modulate heroin addiction via epithalamic innervation in rats

Acta Pharmacologica Sinica volume 45, pages 945–958 (2024)Cite this article

Abstract

Glutamatergic neurons in ventral pallidum (VPGlu) were recently reported to mediate motivational and emotional behavior, but its role in opioid addiction still remains to be elucidated. In this study we investigated the function of VPGlu in the context-dependent heroin taking and seeking behavior in male rats under the ABA renewal paradigm. By use of cell-type-specific fiber photometry, we showed that the calcium activity of VPGlu were inhibited during heroin self-administration and context-induced relapse, but activated after extinction in a new context. The drug seeking behavior was accompanied by the decreased calcium signal of VPGlu. Chemogenetic manipulation of VPGlu bidirectionally regulated heroin taking and seeking behavior. Anterograde tracing showed that the lateral habenula, one of the epithalamic structures, was the major output region of VPGlu, and its neuronal activity was consistent with VPGlu in different phases of heroin addiction and contributed to the motivation for heroin. VPGlu axon terminals in LHb exhibited dynamic activity in different phases of heroin addiction. Activation of VPGlu-LHb circuit reduced heroin seeking behavior during context-induced relapse. Furthermore, the balance of excitation/inhibition from VP to LHb was shifted to enhanced glutamate transmission after extinction of heroin seeking motivation. Overall, the present study demonstrated that the activity of VPGlu was involved in the regulation of heroin addiction and identified the VPGlu-LHb pathway as a potential intervention to reduce heroin seeking motivation.

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Fig. 1: Drug taking and seeking behavior in different phases of heroin addiction.
Fig. 2: Calcium activity of VP glutamatergic neurons during heroin self-administration.
Fig. 3: Calcium activity of VP glutamatergic neurons during extinction and context-induced relapse.
Fig. 4: Chemogenetic activation of VP glutamatergic neurons blocks heroin taking and seeking behavior.
Fig. 5: Chemogenetic inhibition of VP glutamatergic neurons increased heroin seeking motivation.
Fig. 6: Activity of neurons in LHb was involved in the regulation of heroin addiction.
Fig. 7: VPGlu regulated heroin addiction via direct innervation to LHb.
Fig. 8: Extinction of heroin seeking motivation changed the balance of VP glutamate/GABA transmission to LHb.

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Acknowledgements

This research was supported by the Major Project of the Science and Technology Innovation 2030 of China (2021ZD0203500, STI2030-Major Projects 2021ZD0202900); National Natural Science Foundation of China (82030112, 81773710, 82371533, 82301677); Science and Technology Commission of Shanghai Municipality (20ZR1468200); Natural Science Foundation of Shanghai (22ZR1449300); Program of Shanghai Academic/Technology Research Leader (22XD1402400) and Shenzhen-Hong Kong Institute of Brain Science—Shenzhen Fundamental Research Institutions (NYKFKT2019015).

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Author notes

  1. These authors contributed equally: Ruo-song Chen, Jing Liu

Authors and Affiliations

  1. Shanghai Key Laboratory of Maternal Fetal Medicine, Shanghai Institute of Maternal-Fetal Medicine and Gynecologic Oncology, Department of Anesthesiology, Shanghai First Maternity and Infant Hospital, School of Medicine, Tongji University, Shanghai, 201204, China

    Ruo-song Chen & Zhi-qiang Liu

  2. Center for Neurological and Psychiatric Research and Drug Discovery, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, 201203, China

    Ruo-song Chen, Jing Liu, Yu-jun Wang, Kuan Ning & Jing-gen Liu

  3. State Key Laboratory of Natural Medicines, School of Biopharmacy, China Pharmaceutical University, Nanjing, 211198, China

    Jing Liu

  4. School of Chinese Materia Medica, Nanjing University of Chinese Medicine, Nanjing, 210023, China

    Kuan Ning

  5. Key Laboratory of Neuropharmacology and Translational Medicine of Zhejiang Province, School of Pharmaceutical Sciences, Zhejiang Chinese Medical University, Hangzhou, 310053, China

    Jing-gen Liu

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Contributions

ZQL, RSC and JL conceived this study and design the experiment; RSC and JL conducted the experiments with the assistance of YJW and KN; RSC and JL analyzed the data and wrote the manuscript; ZQL and JGL revised the manuscript.

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Correspondence to Jing-gen Liu or Zhi-qiang Liu.

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Chen, Rs., Liu, J., Wang, Yj. et al. Glutamatergic neurons in ventral pallidum modulate heroin addiction via epithalamic innervation in rats. Acta Pharmacol Sin 45, 945–958 (2024). https://doi.org/10.1038/s41401-024-01229-4

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