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.

Autor: Hoffman JL; 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., Faccidomo SP; 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.; Department of Psychiatry, School of Medicine, University of North Carolina at Chapel Hill, Chapel Hill, NC, 27599, USA., Taylor SM; 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., DeMiceli KG; 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., May AM; 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., Smith EN; 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., Whindleton CM; 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., Hodge CW; 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. chodge@med.unc.edu.; Department of Psychiatry, School of Medicine, University of North Carolina at Chapel Hill, Chapel Hill, NC, 27599, USA. chodge@med.unc.edu.; Department of Pharmacology, School of Medicine, University of North Carolina at Chapel Hill, Chapel Hill, NC, 27599, USA. chodge@med.unc.edu.
Jazyk: angličtina
Zdroj: Psychopharmacology [Psychopharmacology (Berl)] 2023 Jun; Vol. 240 (6), pp. 1261-1273. Date of Electronic Publication: 2023 Apr 13.
DOI: 10.1007/s00213-023-06365-z
Abstrakt: 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.
(© 2023. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)
Databáze: MEDLINE
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