title: The smoking cessation drug varenicline improves deficient P20-N40 inhibition in DBA/2 mice.
abstract: Varenicline, an FDA approved smoking cessation pharmacotherapy, is an α4β2* nicotinic acetylcholine receptor (nAChR) partial agonist and an α7* nAChR full agonist. Both subtypes of nAChR are involved in modulating auditory evoked responses in rodents. In DBA/2 mice, an inbred strain, auditory evoked responses to paired auditory stimuli fail to inhibit to the second stimulus. This mouse strain replicates the auditory evoked response inhibition deficit experienced by the majority of schizophrenia patients. In this current study, we examined the effects of five different doses of varenicline (0.06, 0.3, 0.6, 3 and 6mg/kg) on auditory evoked responses in anesthetized DBA/2 mice. We also administered α4β2* and α7* nAChR selective antagonists prior to varenicline administration to determine which nAChR subtypes mediate the effects of varenicline. Four of the five doses of varenicline produced improvements in auditory evoked response inhibition deficits. Selective blockade of either the α4β2* or α7* nAChR in competition with 0.6mg/kg varenicline prevented varenicline induced improvements. In competition with a higher dose of varenicline (3mg/kg) only blockade of the α4β2* nAChR prevented varenicline induced improvement in auditory evoked response inhibition. These data indicate the importance of α4β2* nAChRs and the potential involvement of the α7* subtype in varenicline's effects on auditory evoked responses in DBA/2 mice.
authors.affiliation: Medical Research, Veterans Affairs Medical Center, Denver, CO 80220, USA. Kristin.Andrud@ucdenver.edu
authors.forename: Kristin M
authors.initials: KM
authors.lastname: Wildeboer-Andrud
authors.forename: Karen E
authors.initials: KE
authors.lastname: Stevens
mesh_terms: D000161:Acoustic Stimulation / Q000379:methods*; D000818:Animals; D001552:Benzazepines / Q000494:pharmacology*; D005072:Evoked Potentials, Auditory / Q000187:drug effects / Q000502:physiology*; D008297:Male; D051379:Mice; D008811:Mice, Inbred DBA; D009433:Neural Inhibition / Q000187:drug effects / Q000235:genetics*; D018722:Nicotinic Agonists / Q000494:pharmacology*; D018733:Nicotinic Antagonists / Q000494:pharmacology; D010446:Peptide Fragments / Q000172:deficiency* / Q000502:physiology; D011810:Quinoxalines / Q000494:pharmacology*; D011978:Receptors, Nicotinic / Q000235:genetics* / Q000502:physiology; D016540:Smoking Cessation / Q000379:methods; D000068580:Varenicline; D064569:alpha7 Nicotinic Acetylcholine Receptor
chemical_list: D001552:Benzazepines; C579166:Chrna7 protein, mouse; D018722:Nicotinic Agonists; D018733:Nicotinic Antagonists; D010446:Peptide Fragments; D011810:Quinoxalines; D011978:Receptors, Nicotinic; D064569:alpha7 Nicotinic Acetylcholine Receptor; C403531:nicotinic receptor alpha4beta2; D000068580:Varenicline