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Distinct Synaptic Strengthening of the Striatal Direct and Indirect Pathways Drives Alcohol Consumption

  • Author Footnotes
    1 YC, CCYH, and TM contributed equally to this work.
    Yifeng Cheng
    Footnotes
    1 YC, CCYH, and TM contributed equally to this work.
    Affiliations
    Department of Neuroscience and Experimental Therapeutics, College of Medicine, Texas A&M Health Science Center, Bryan, Texas
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  • Author Footnotes
    1 YC, CCYH, and TM contributed equally to this work.
    Cathy C.Y. Huang
    Footnotes
    1 YC, CCYH, and TM contributed equally to this work.
    Affiliations
    Department of Neuroscience and Experimental Therapeutics, College of Medicine, Texas A&M Health Science Center, Bryan, Texas
    Search for articles by this author
  • Author Footnotes
    1 YC, CCYH, and TM contributed equally to this work.
    Tengfei Ma
    Footnotes
    1 YC, CCYH, and TM contributed equally to this work.
    Affiliations
    Department of Neuroscience and Experimental Therapeutics, College of Medicine, Texas A&M Health Science Center, Bryan, Texas
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  • Xiaoyan Wei
    Affiliations
    Department of Neuroscience and Experimental Therapeutics, College of Medicine, Texas A&M Health Science Center, Bryan, Texas
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  • Xuehua Wang
    Affiliations
    Department of Neuroscience and Experimental Therapeutics, College of Medicine, Texas A&M Health Science Center, Bryan, Texas
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  • Jiayi Lu
    Affiliations
    Department of Neuroscience and Experimental Therapeutics, College of Medicine, Texas A&M Health Science Center, Bryan, Texas
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  • Jun Wang
    Correspondence
    Address correspondence to: Jun Wang, M.D., Ph.D., Texas A&M Health Science Center, Neuroscience and Experimental Therapeutics, 8447 State Highway 47, Suite 2106, Bryan, Texas 77807.
    Affiliations
    Department of Neuroscience and Experimental Therapeutics, College of Medicine, Texas A&M Health Science Center, Bryan, Texas
    Search for articles by this author
  • Author Footnotes
    1 YC, CCYH, and TM contributed equally to this work.

      Abstract

      Background

      Repeated exposure to addictive drugs or alcohol triggers glutamatergic and gamma-aminobutyric acidergic (GABAergic) plasticity in many neuronal populations. The dorsomedial striatum (DMS), a brain region critically involved in addiction, contains medium spiny neurons (MSNs) expressing dopamine D1 or D2 receptors, which form direct and indirect pathways, respectively. It is unclear how alcohol-evoked plasticity in the DMS contributes to alcohol consumption in a cell type–specific manner.

      Methods

      Mice were trained to consume alcohol using an intermittent-access two-bottle-choice drinking procedure. Slice electrophysiology was used to measure glutamatergic and GABAergic strength in DMS D1- and D2-MSNs of alcohol-drinking mice and control mice. In vivo chemogenetic and pharmacologic approaches were employed to manipulate MSN activity, and their consequences on alcohol consumption were measured.

      Results

      Repeated cycles of alcohol consumption and withdrawal in mice strengthened glutamatergic transmission in D1-MSNs and GABAergic transmission in D2-MSNs. In vivo chemogenetic excitation of D1-MSNs, mimicking glutamatergic strengthening, promoted alcohol consumption; the same effect was induced by D2-MSN inhibition, mimicking GABAergic strengthening. Importantly, suppression of GABAergic transmission via D2 receptor–glycogen synthase kinase–3β signaling dramatically reduced excessive alcohol consumption, as did selective inhibition of D1-MSNs or excitation of D2-MSNs.

      Conclusions

      Our results suggest that repeated cycles of excessive alcohol intake and withdrawal potentiate glutamatergic strength exclusively in D1-MSNs and GABAergic strength specifically in D2-MSNs of the DMS, which concurrently contribute to alcohol consumption. These results provide insight into the synaptic and cell type–specific mechanisms underlying alcohol addiction and identify targets for the development of new therapeutic approaches to alcohol abuse.

      Keywords

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      Linked Article

      • Tipping the Scales Toward Addiction
        Biological PsychiatryVol. 81Issue 11
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          Despite diverse acute pharmacological actions, all drugs of abuse produce many similar behaviors, such as psychomotor sensitization, conditioned drug taking, drug seeking, and relapse (1). The development of these addiction-related behaviors is thought to arise from diverse molecular and cellular adaptations, which collectively result in convergent long-term functional alterations of the striatum. However, at the cellular level, on the one hand, exposure to different classes of drugs, such as stimulants versus opioids (2), induces distinct and often opposing forms of adaptations in striatal medium spiny neurons (MSNs).
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