Calcium-permeable AMPA receptor activity and GluA1 trafficking in the basolateral amygdala regulate operant alcohol self-administration.

Autor:	Faccidomo S; Bowles Center for Alcohol Studies, The University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA.; Department of Psychiatry, The University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA., Cogan ES; Bowles Center for Alcohol Studies, The University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA., Hon OJ; Bowles Center for Alcohol Studies, The University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA.; Neuroscience Curriculum, The University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA., Hoffman JL; Bowles Center for Alcohol Studies, The University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA., Saunders BL; Bowles Center for Alcohol Studies, The University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA., Eastman VR; Bowles Center for Alcohol Studies, The University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA., Kim M; Bowles Center for Alcohol Studies, The University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA., Taylor SM; Bowles Center for Alcohol Studies, The University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA., McElligott ZA; Bowles Center for Alcohol Studies, The University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA.; Department of Psychiatry, The University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA.; Department of Pharmacology, The University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA., Hodge CW; Bowles Center for Alcohol Studies, The University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA.; Department of Psychiatry, The University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA.; Department of Pharmacology, The University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA.
Jazyk:	angličtina
Zdroj:	Addiction biology [Addict Biol] 2021 Sep; Vol. 26 (5), pp. e13049. Date of Electronic Publication: 2021 May 05.
DOI:	10.1111/adb.13049
Abstrakt:	Addiction is viewed as maladaptive glutamate-mediated neuroplasticity that is regulated, in part, by calcium-permeable AMPA receptor (CP-AMPAR) activity. However, the contribution of CP-AMPARs to alcohol-seeking behavior remains to be elucidated. We evaluated CP-AMPAR activity in the basolateral amygdala (BLA) as a potential target of alcohol that also regulates alcohol self-administration in C57BL/6J mice. Operant self-administration of sweetened alcohol increased spontaneous EPSC frequency in BLA neurons that project to the nucleus accumbens as compared with behavior-matched sucrose controls indicating an alcohol-specific upregulation of synaptic activity. Bath application of the CP-AMPAR antagonist NASPM decreased evoked EPSC amplitude only in alcohol self-administering mice indicating alcohol-induced synaptic insertion of CP-AMPARs in BLA projection neurons. Moreover, NASPM infusion in the BLA dose-dependently decreased the rate of operant alcohol self-administration providing direct evidence for CP-AMPAR regulation of alcohol reinforcement. As most CP-AMPARs are GluA1-containing, we asked if alcohol alters the activation state of GluA1-containing AMPARs. Immunocytochemistry results showed elevated GluA1-S831 phosphorylation in the BLA of alcohol as compared with sucrose mice. To investigate mechanistic regulation of alcohol self-administration by GluA1-containing AMPARs, we evaluated the necessity of GluA1 trafficking using a TET-ON AAV encoding a dominant-negative GluA1 c-terminus (GluA1ct) that blocks activity-dependent synaptic delivery of native GluA1-containing AMPARs. GluA1ct expression in the BLA reduced alcohol self-administration with no effect on sucrose controls. These results show that CP-AMPAR activity and GluA1 trafficking in the BLA mechanistically regulate the reinforcing effects of sweetened alcohol. Pharmacotherapeutic targeting these mechanisms of maladaptive neuroplasticity may aid medical management of alcohol use disorder. (© 2021 Society for the Study of Addiction.)
Databáze:	MEDLINE
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