title: Nicotine withdrawal-induced inattention is absent in alpha7 nAChR knockout mice.
abstract: Smoking is the leading cause of preventable death in the USA, but quit attempts result in withdrawal-induced cognitive dysfunction and predicts relapse. Greater understanding of the neural mechanism(s) underlying these cognitive deficits is required to develop targeted treatments to aid quit attempts.
  
  
  
  We examined nicotine withdrawal-induced inattention in mice lacking the α7 nicotinic acetylcholine receptor (nAChR) using the five-choice continuous performance test (5C-CPT).
  
  
  
  Mice were trained in the 5C-CPT prior to osmotic minipump implantation containing saline or nicotine. Experiment 1 used 40 mg kg-1day-1nicotine treatment and tested C57BL/6 mice 4, 28, and 52 h after pump removal. Experiment 2 used 14 and 40 mg kg-1day-1nicotine treatment in α7 nAChR knockout (KO) and wildtype (WT) littermates tested 4 h after pump removal. Subsets of WT mice were killed before and after pump removal to assess changes in receptor expression associated with nicotine administration and withdrawal.
  
  
  
  Nicotine withdrawal impaired attention in the 5C-CPT, driven by response inhibition and target detection deficits. The overall attentional deficit was absent in α7 nAChR KO mice despite response disinhibition in these mice. Synaptosomal glutamate mGluR5 and dopamine D4receptor expression were reduced during chronic nicotine but increased during withdrawal, potentially contributing to cognitive deficits.
  
  
  
  The α7 nAChR may underlie nicotine withdrawal-induced deficits in target detection but is not required for response disinhibition deficits. Alterations to the glutamatergic and dopaminergic pathways may also contribute to withdrawal-induced attentional deficits, providing novel targets to alleviate the cognitive symptoms of withdrawal during quit attempts.
authors.affiliation: Department of Psychiatry, University of California San Diego, 9500 Gilman Drive MC 0804, La Jolla, CA, 92093-0804, USA.
authors.forename: K K
authors.initials: KK
authors.lastname: Higa
authors.affiliation: Department of Psychiatry, University of California San Diego, 9500 Gilman Drive MC 0804, La Jolla, CA, 92093-0804, USA.
authors.forename: A
authors.initials: A
authors.lastname: Grim
authors.affiliation: Department of Psychiatry, University of California San Diego, 9500 Gilman Drive MC 0804, La Jolla, CA, 92093-0804, USA.
authors.forename: M E
authors.initials: ME
authors.lastname: Kamenski
authors.affiliation: Department of Psychiatry, University of California San Diego, 9500 Gilman Drive MC 0804, La Jolla, CA, 92093-0804, USA.
authors.forename: J
authors.initials: J
authors.lastname: van Enkhuizen
authors.affiliation: Department of Psychiatry, University of California San Diego, 9500 Gilman Drive MC 0804, La Jolla, CA, 92093-0804, USA.|Research Service, VA San Diego Healthcare System, 3350 La Jolla Village Drive, San Diego, CA, 92037, USA.
authors.forename: X
authors.initials: X
authors.lastname: Zhou
authors.affiliation: Department of Medicine, University of California San Diego, 9500 Gilman Drive, La Jolla, CA, 92093, USA.
authors.forename: K
authors.initials: K
authors.lastname: Li
authors.affiliation: Department of Psychiatry, University of California San Diego, 9500 Gilman Drive MC 0804, La Jolla, CA, 92093-0804, USA.
authors.forename: J C
authors.initials: JC
authors.lastname: Naviaux
authors.affiliation: Department of Medicine, University of California San Diego, 9500 Gilman Drive, La Jolla, CA, 92093, USA.
authors.forename: L
authors.initials: L
authors.lastname: Wang
authors.affiliation: Department of Medicine, University of California San Diego, 9500 Gilman Drive, La Jolla, CA, 92093, USA.
authors.forename: R K
authors.initials: RK
authors.lastname: Naviaux
authors.affiliation: Department of Psychiatry, University of California San Diego, 9500 Gilman Drive MC 0804, La Jolla, CA, 92093-0804, USA.|Research Service, VA San Diego Healthcare System, 3350 La Jolla Village Drive, San Diego, CA, 92037, USA.
authors.forename: M A
authors.initials: MA
authors.lastname: Geyer
authors.affiliation: Department of Psychiatry, University of California San Diego, 9500 Gilman Drive MC 0804, La Jolla, CA, 92093-0804, USA.
authors.forename: A
authors.initials: A
authors.lastname: Markou
authors.affiliation: Department of Psychiatry, University of California San Diego, 9500 Gilman Drive MC 0804, La Jolla, CA, 92093-0804, USA. jaredyoung@ucsd.edu.|Research Service, VA San Diego Healthcare System, 3350 La Jolla Village Drive, San Diego, CA, 92037, USA. jaredyoung@ucsd.edu.
authors.forename: J W
authors.initials: JW
authors.lastname: Young
mesh_terms: D000818:Animals; D001288:Attention / Q000187:drug effects / Q000502:physiology*; D002755:Choice Behavior / Q000187:drug effects / Q000502:physiology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009538:Nicotine / Q000008:administration & dosage* / Q000009:adverse effects*; D011597:Psychomotor Performance / Q000187:drug effects / Q000502:physiology*; D013375:Substance Withdrawal Syndrome / Q000378:metabolism* / Q000523:psychology; D013574:Synaptosomes / Q000187:drug effects / Q000378:metabolism; D064569:alpha7 Nicotinic Acetylcholine Receptor / Q000819:agonists / Q000172:deficiency*
chemical_list: D064569:alpha7 Nicotinic Acetylcholine Receptor; D009538:Nicotine
keywords: Attention; Dopamine D4 receptor; Five-choice continuous performance task; Response inhibition; mGluR5; α7 Nicotinic acetylcholine receptor