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Activation of Kv7 channels normalizes hyperactivity of the VTA-NAcLat circuit and attenuates methamphetamine-induced conditioned place preference and sensitization in mice

Molecular Psychiatry volume 28, pages 5183–5194 (2023)Cite this article

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Abstract

The brain circuit projecting from the ventral tegmental area (VTA) to the nucleus accumbens lateral shell (NAcLat) has a key role in methamphetamine (MA) addiction. As different dopamine (DA) neuron subpopulations in the VTA participate in different neuronal circuits, it is a challenge to isolate these DA neuron subtypes. Using retrograde tracing and Patch-seq, we isolated DA neurons in the VTA-NAcLat circuit in MA-treated mice and performed gene expression profiling. Among the differentially expressed genes, KCNQ genes were dramatically downregulated. KCNQ genes encode Kv7 channel proteins, which modulate neuronal excitability. Injection of both the Kv7.2/3 agonist ICA069673 and the Kv7.4 agonist fasudil into the VTA attenuated MA-induced conditioned place preference and locomotor sensitization and decreased neuronal excitability. Increasing Kv7.2/3 activity decreased neural oscillations, synaptic plasticity and DA release in the VTA-NacLat circuit in MA-treated mice. Furthermore, overexpression of only Kv7.3 channels in the VTA-NacLat circuit was sufficient to attenuate MA-induced reward behavior and decrease VTA neuron excitability. Activation of Kv7 channels in the VTA may become a novel treatment strategy for MA abuse.

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Fig. 1: Anatomical organization of VTA neurons projecting to the NAcLat.
Fig. 2: Single-cell RNA-seq analysis of DA neurons in the VTA-NAcLat circuit in mice treated with MA.
Fig. 3: Activation of Kv7 channels reduces the addictive potential of MA and modulates the cellular excitability of VTA neurons in MA-treated mice.
Fig. 4: Activation of Kv7.2/3 channels reduces neuronal oscillations and the levels of Arc in MA-treated mice.
Fig. 5: Effects of Kv7.2/3 channel activation on DA release into the NAcLat and synaptic plasticity in the VTA-NAcLat circuit.
Fig. 6: Overexpression of Kv7.3 channels rescues behavioral and electrophysiological changes induced by MA in mice.

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Acknowledgements

We thank the Translational Medicine Core Facility of Shandong University for consultation and instrument availability that supported this work.

Funding

This study was supported by the National Natural Science Foundation of China, Grant Number: U220011 and 81871044.

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Authors and Affiliations

  1. Department of Anatomy and Neurobiology, Shandong University School of Basic Medicine, Jinan, Shandong, China

    E Liu, Kunkun Pang, Min Liu, Xu Tan, Zhaofang Hang, Shouhong Mu, Weikai Han, Qingwei Yue & Jinhao Sun

  2. Department of Ultrasound, The Second Hospital of Shandong University, Jinan, Shandong, China

    Kunkun Pang

  3. Department of Psychiatry, McGill University, Montréal, QC, Canada

    Stefano Comai

  4. Department of Pharmaceutical and Pharmacological Sciences, University of Padua, Padua, Italy

    Stefano Comai

  5. Department of Biomedical Sciences, University of Padua, Padua, Italy

    Stefano Comai

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JS and EL designed this experiment and prepared the manuscript. EL also performed experiments and wrote the draft. KP, ML, XT, RS, ZH, SM and WH participated in some of the experiments and analyzed the data. SC provided critical revision for important intellectual content and revised the manuscript draft. All authors reviewed and approved the manuscript.

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Liu, E., Pang, K., Liu, M. et al. Activation of Kv7 channels normalizes hyperactivity of the VTA-NAcLat circuit and attenuates methamphetamine-induced conditioned place preference and sensitization in mice. Mol Psychiatry 28, 5183–5194 (2023). https://doi.org/10.1038/s41380-023-02218-5

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