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Negative modulation of AMPA receptors bound to transmembrane AMPA receptor regulatory protein γ-8 blunts the positive reinforcing properties of alcohol and sucrose in a brain region-dependent manner in male mice

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Abstract

Rationale

The development and progression of alcohol use disorder (AUD) are widely viewed as maladaptive neuroplasticity. The transmembrane alpha-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid receptor (AMPAR) regulatory protein γ8 (TARP γ-8) is a molecular mechanism of neuroplasticity that has not been evaluated in AUD or other addictions.

Objective

To address this gap in knowledge, we evaluated the mechanistic role of TARP γ-8 bound AMPAR activity in the basolateral amygdala (BLA) and ventral hippocampus (vHPC) in the positive reinforcing effects of alcohol, which drive repetitive alcohol use throughout the course of AUD, in male C57BL/6 J mice. These brain regions were selected because they exhibit high levels of TARP γ-8 expression and send glutamate projections to the nucleus accumbens (NAc), which is a key nucleus in the brain reward pathway.

Methods and results

Site-specific pharmacological inhibition of AMPARs bound to TARP γ-8 in the BLA via bilateral infusion of the selective negative modulator JNJ-55511118 (0–2 µg/µl/side) significantly decreased operant alcohol self-administration with no effect on sucrose self-administration in behavior-matched controls. Temporal analysis showed that reductions in alcohol-reinforced response rate occurred > 25 min after the onset of responding, consistent with a blunting of the positive reinforcing effects of alcohol in the absence of nonspecific behavioral effects. In contrast, inhibition of TARP γ-8 bound AMPARs in the vHPC selectively decreased sucrose self-administration with no effect on alcohol.

Conclusions

This study reveals a novel brain region-specific role of TARP γ-8 bound AMPARs as a molecular mechanism of the positive reinforcing effects of alcohol and non-drug rewards.

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Data availability

Data from this study are available from the corresponding author upon reasonable request.

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Acknowledgements

The authors wish to thank our dedicated team of undergraduate research assistants and research technicians for their assistance. Specifically, we thank Eric Homberger, Julie Lee, and LC Wong for their help with behavioral tasks and laboratory upkeep.

Funding

Research reported in this publication was supported by the National Institute on Alcohol Abuse and Alcoholism of the National Institutes of Health under award numbers R01 AA028782 (CWH), P60 AA011605 (CWH), and F32 AA028993 (JLH), and by the Bowles Center for Alcohol Studies at The University of North Carolina at Chapel Hill.

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Authors and Affiliations

  1. Bowles Center for Alcohol Studies, School of Medicine, University of North Carolina at Chapel Hill, Thurston-Bowles Building, CB#7178, Chapel Hill, NC, 27599, USA

    Jessica L. Hoffman, Sara P. Faccidomo, Seth M. Taylor, Kristina G. DeMiceli, Ashley M. May, Evan N. Smith, Ciarra M. Whindleton & Clyde W. Hodge

  2. Department of Psychiatry, School of Medicine, University of North Carolina at Chapel Hill, Chapel Hill, NC, 27599, USA

    Sara P. Faccidomo & Clyde W. Hodge

  3. Department of Pharmacology, School of Medicine, University of North Carolina at Chapel Hill, Chapel Hill, NC, 27599, USA

    Clyde W. Hodge

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  1. Jessica L. Hoffman
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Contributions

JLH, SF, and CWH designed the experiments. JLH, SF, and KGD performed the surgeries. JLH, SMT, KGD, AMM, and ENS performed the experiments. JLH and CWH analyzed the data. JLH, SF, CMW, and CWH interpreted the data, wrote, and edited the manuscript.

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Correspondence to Clyde W. Hodge.

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Hoffman, J.L., Faccidomo, S.P., Taylor, S.M. et al. Negative modulation of AMPA receptors bound to transmembrane AMPA receptor regulatory protein γ-8 blunts the positive reinforcing properties of alcohol and sucrose in a brain region-dependent manner in male mice. Psychopharmacology 240, 1261–1273 (2023). https://doi.org/10.1007/s00213-023-06365-z

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