KCNN genes that encode small-conductance Ca 2+-activated K+ channels influence alcohol and drug addiction

Audrey E. Padula, William C. Griffin, Marcelo F. Lopez, Sudarat Nimitvilai, Reginald Cannady, Natalie S. McGuier, Elissa J. Chesler, Michael F. Miles, Robert Williams, Patrick K. Randall, John J. Woodward, Howard C. Becker, Patrick J. Mulholland

Research output: Contribution to journalArticle

17 Citations (Scopus)

Abstract

Small-conductance Ca 2+-activated K+ (K Ca2) 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. K Ca 2.3 channels represent a promising novel target in the pharmacogenetic treatment of alcohol and drug addiction.

Original languageEnglish (US)
Pages (from-to)1928-1939
Number of pages12
JournalNeuropsychopharmacology
Volume40
Issue number8
DOIs
StatePublished - Jul 13 2015

Fingerprint

Alcoholism
Nucleus Accumbens
Substance-Related Disorders
Alcohols
Genes
Apamin
Neuronal Plasticity
Nicotine
Alcohol Drinking
Pharmacogenetics
Microinjections
Street Drugs
Genomics
Inbred C57BL Mouse
Seizures
Neurons
Injections
Proteins

All Science Journal Classification (ASJC) codes

  • Pharmacology
  • Psychiatry and Mental health

Cite this

Padula, A. E., Griffin, W. C., Lopez, M. F., Nimitvilai, S., Cannady, R., McGuier, N. S., ... Mulholland, P. J. (2015). KCNN genes that encode small-conductance Ca 2+-activated K+ channels influence alcohol and drug addiction. Neuropsychopharmacology, 40(8), 1928-1939. https://doi.org/10.1038/npp.2015.42

KCNN genes that encode small-conductance Ca 2+-activated K+ channels influence alcohol and drug addiction. / Padula, Audrey E.; Griffin, William C.; Lopez, Marcelo F.; Nimitvilai, Sudarat; Cannady, Reginald; McGuier, Natalie S.; Chesler, Elissa J.; Miles, Michael F.; Williams, Robert; Randall, Patrick K.; Woodward, John J.; Becker, Howard C.; Mulholland, Patrick J.

In: Neuropsychopharmacology, Vol. 40, No. 8, 13.07.2015, p. 1928-1939.

Research output: Contribution to journalArticle

Padula, AE, Griffin, WC, Lopez, MF, Nimitvilai, S, Cannady, R, McGuier, NS, Chesler, EJ, Miles, MF, Williams, R, Randall, PK, Woodward, JJ, Becker, HC & Mulholland, PJ 2015, 'KCNN genes that encode small-conductance Ca 2+-activated K+ channels influence alcohol and drug addiction', Neuropsychopharmacology, vol. 40, no. 8, pp. 1928-1939. https://doi.org/10.1038/npp.2015.42
Padula AE, Griffin WC, Lopez MF, Nimitvilai S, Cannady R, McGuier NS et al. KCNN genes that encode small-conductance Ca 2+-activated K+ channels influence alcohol and drug addiction. Neuropsychopharmacology. 2015 Jul 13;40(8):1928-1939. https://doi.org/10.1038/npp.2015.42
Padula, Audrey E. ; Griffin, William C. ; Lopez, Marcelo F. ; Nimitvilai, Sudarat ; Cannady, Reginald ; McGuier, Natalie S. ; Chesler, Elissa J. ; Miles, Michael F. ; Williams, Robert ; Randall, Patrick K. ; Woodward, John J. ; Becker, Howard C. ; Mulholland, Patrick J. / KCNN genes that encode small-conductance Ca 2+-activated K+ channels influence alcohol and drug addiction. In: Neuropsychopharmacology. 2015 ; Vol. 40, No. 8. pp. 1928-1939.
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