Cell Reports
Volume 23, Issue 1, 3 April 2018, Pages 68-77
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Article
Adolescent Nicotine Exposure Alters GABAA Receptor Signaling in the Ventral Tegmental Area and Increases Adult Ethanol Self-Administration

https://doi.org/10.1016/j.celrep.2018.03.030Get rights and content
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Highlights

  • Adolescent nicotine exposure increases alcohol self-administration in adulthood

  • Adolescent nicotine exposure increases alcohol-induced VTA GABA release

  • Adolescent nicotine exposure impairs chloride extrusion in VTA GABA neurons

  • Enhancing Cl extrusion restores alcohol self-administration to control levels

Summary

Adolescent smoking is associated with pathological drinking later in life, but the biological basis for this vulnerability is unknown. To examine how adolescent nicotine exposure influences subsequent ethanol intake, nicotine was administered during adolescence or adulthood, and responses to alcohol were measured 1 month later. We found that adolescent, but not adult, nicotine exposure altered GABA signaling within the ventral tegmental area (VTA) and led to a long-lasting enhancement of alcohol self-administration. We detected depolarizing shifts in GABAA reversal potentials arising from impaired chloride extrusion in VTA GABA neurons. Alterations in GABA signaling were dependent on glucocorticoid receptor activation and were associated with attenuated dopaminergic neuron responses to alcohol in the lateral VTA. Importantly, enhancing chloride extrusion in adolescent nicotine-treated animals restored VTA GABA signaling and alcohol self-administration to control levels. Taken together, this work suggests that adolescent nicotine exposure increases the risk profile for increased alcohol drinking in adulthood.

Keywords

alcohol use disorder
reward
mesolimbic
nucleus accumbens
self-administration
chloride gradient
KCC2
glucocorticoid
gateway
dopamine

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