Adolescent Nicotine Exposure Alters GABAA Receptor Signaling in the Ventral Tegmental Area and Increases Adult Ethanol Self-Administration

Cell Rep. 2018 Apr 3;23(1):68-77. doi: 10.1016/j.celrep.2018.03.030.

Abstract

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

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Animals
  • Dopaminergic Neurons / drug effects
  • Dopaminergic Neurons / metabolism
  • Dopaminergic Neurons / physiology
  • Ethanol / administration & dosage
  • Ethanol / pharmacology*
  • GABAergic Neurons / drug effects
  • GABAergic Neurons / metabolism
  • GABAergic Neurons / physiology
  • Male
  • Nicotine / pharmacology*
  • Rats
  • Rats, Long-Evans
  • Receptors, GABA-A / metabolism*
  • Receptors, Glucocorticoid / metabolism
  • Self Administration
  • Synaptic Potentials*
  • Ventral Tegmental Area / drug effects*
  • Ventral Tegmental Area / growth & development

Substances

  • Receptors, GABA-A
  • Receptors, Glucocorticoid
  • Ethanol
  • Nicotine