KCNN Genes That Encode Small-Conductance Ca2+-Activated K+ Channels Influence Alcohol and Drug Addiction

Neuropsychopharmacology. 2015 Jul;40(8):1928-39. doi: 10.1038/npp.2015.42. Epub 2015 Feb 9.

Abstract

Small-conductance Ca(2+)-activated K(+) (KCa2) channels control neuronal excitability and synaptic plasticity, and have been implicated in substance abuse. However, it is unknown if genes that encode KCa2 channels (KCNN1-3) influence alcohol and drug addiction. In the present study, an integrative functional genomics approach shows that genetic datasets for alcohol, nicotine, and illicit drugs contain the family of KCNN genes. Alcohol preference and dependence QTLs contain KCNN2 and KCNN3, and Kcnn3 transcript levels in the nucleus accumbens (NAc) of genetically diverse BXD strains of mice predicted voluntary alcohol consumption. Transcript levels of Kcnn3 in the NAc negatively correlated with alcohol intake levels in BXD strains, and alcohol dependence enhanced the strength of this association. Microinjections of the KCa2 channel inhibitor apamin into the NAc increased alcohol intake in control C57BL/6J mice, while spontaneous seizures developed in alcohol-dependent mice following apamin injection. Consistent with this finding, alcohol dependence enhanced the intrinsic excitability of medium spiny neurons in the NAc core and reduced the function and protein expression of KCa2 channels in the NAc. Altogether, these data implicate the family of KCNN genes in alcohol, nicotine, and drug addiction, and identify KCNN3 as a mediator of voluntary and excessive alcohol consumption. KCa2.3 channels represent a promising novel target in the pharmacogenetic treatment of alcohol and drug addiction.

Publication types

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

MeSH terms

  • Alcoholism / etiology
  • Alcoholism / genetics*
  • Analysis of Variance
  • Animals
  • Apamin / toxicity
  • Central Nervous System Depressants / toxicity
  • Choice Behavior / drug effects
  • Computational Biology
  • Conditioning, Operant / drug effects
  • Dose-Response Relationship, Drug
  • Electric Stimulation
  • Ethanol / administration & dosage
  • Female
  • Humans
  • In Vitro Techniques
  • Linear Models
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Mice, Mutant Strains
  • Microarray Analysis / statistics & numerical data
  • Microinjections
  • Nucleus Accumbens / cytology
  • Nucleus Accumbens / drug effects
  • Patch-Clamp Techniques
  • Potassium Channel Blockers / toxicity
  • Quantitative Trait Loci
  • Small-Conductance Calcium-Activated Potassium Channels / classification
  • Small-Conductance Calcium-Activated Potassium Channels / genetics*
  • Small-Conductance Calcium-Activated Potassium Channels / metabolism
  • Substance-Related Disorders / genetics*
  • Synaptic Transmission / drug effects
  • Synaptic Transmission / genetics

Substances

  • Central Nervous System Depressants
  • Potassium Channel Blockers
  • Small-Conductance Calcium-Activated Potassium Channels
  • Apamin
  • Ethanol