title: Dissociation between duration of action in the forced swim test in mice and nicotinic acetylcholine receptor occupancy with sazetidine, varenicline, and 5-I-A85380.
abstract: BACKGROUND
  Nicotinic acetylcholine receptor (nAChR) agonists, partial agonists, and antagonists have antidepressant-like effects in rodents and reduce symptoms of depression in humans.
  
  
  OBJECTIVE
  The study determined whether the antidepressant-like effect of the nAChR β2* partial agonist sazetidine-A (sazetidine) in the forced swim test was due to activation or desensitization of β2* nAChRs. The study also determined if sazetidine's behavioral responses in the forced swim test corresponded to β2* nAChRs receptor occupancy and drug bioavailability.
  
  
  RESULTS
  Acute antidepressant-like effects in the forced swim test were seen with sazetidine and the full β2* agonist 5-I-A8350 (BALB/cJ mice) and the less selective β2* partial agonist varenicline in C57BL/6J but not BALB/cJ mice. The role of β2* nAChRs was confirmed by results showing: (1) reversal of sazetidine's antidepressant-like effects in the forced swim test by nAChR antagonists mecamylamine and dihydro-β-erythroidine; (2) absence of sazetidine's effect in mice lacking the β2 subunit of the nAChR; and (3) a high correspondence between behaviorally active doses of sazetidine and β2* receptor occupancy. β2* receptor occupancy following acute sazetidine, varenicline, and 5-I-A8350 lasted beyond the duration of action in the forced swim test. Sazetidine's long lasting receptor occupancy did not diminish behavioral efficacy in the forced swim test following repeated dosing.
  
  
  CONCLUSIONS
  Results demonstrate that activation of a small population of β2* nAChRs (10-40%) is sufficient to elicit sazetidine's antidepressant-like actions without producing tolerance and suggest that ligands that activate β2* nAChRs would be promising targets for the development of a new class of antidepressant.
authors.affiliation: PsychoGenics, Inc., 765 Old Saw Mill River Road, Tarrytown, NY 10591, USA. Barbara.Caldarone@gmail.com
authors.forename: Barbara J
authors.initials: BJ
authors.lastname: Caldarone
authors.forename: Daguang
authors.initials: D
authors.lastname: Wang
authors.forename: Neil E
authors.initials: NE
authors.lastname: Paterson
authors.forename: Michael
authors.initials: M
authors.lastname: Manzano
authors.forename: Allison
authors.initials: A
authors.lastname: Fedolak
authors.forename: Katie
authors.initials: K
authors.lastname: Cavino
authors.forename: Mei
authors.initials: M
authors.lastname: Kwan
authors.forename: Taleen
authors.initials: T
authors.lastname: Hanania
authors.forename: Sheela K
authors.initials: SK
authors.lastname: Chellappan
authors.forename: Alan P
authors.initials: AP
authors.lastname: Kozikowski
authors.forename: Berend
authors.initials: B
authors.lastname: Olivier
authors.forename: Marina R
authors.initials: MR
authors.lastname: Picciotto
authors.forename: Afshin
authors.initials: A
authors.lastname: Ghavami
mesh_terms: D000818:Animals; D000928:Antidepressive Agents / Q000097:blood / Q000493:pharmacokinetics / Q000494:pharmacology*; D001384:Azetidines / Q000097:blood / Q000493:pharmacokinetics / Q000494:pharmacology*; D001522:Behavior, Animal / Q000187:drug effects; D001552:Benzazepines / Q000097:blood / Q000493:pharmacokinetics / Q000494:pharmacology*; D001921:Brain / Q000378:metabolism; D003627:Data Interpretation, Statistical; D004305:Dose-Response Relationship, Drug; D008024:Ligands; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D015394:Molecular Structure; D009043:Motor Activity / Q000187:drug effects; D018722:Nicotinic Agonists / Q000097:blood / Q000493:pharmacokinetics / Q000494:pharmacology*; D011485:Protein Binding; D011725:Pyridines / Q000097:blood / Q000493:pharmacokinetics / Q000494:pharmacology*; D011810:Quinoxalines / Q000097:blood / Q000493:pharmacokinetics / Q000494:pharmacology*; D011978:Receptors, Nicotinic / Q000378:metabolism*; D013550:Swimming; D013997:Time Factors; D000068580:Varenicline
chemical_list: D000928:Antidepressive Agents; D001384:Azetidines; D001552:Benzazepines; D008024:Ligands; D018722:Nicotinic Agonists; D011725:Pyridines; D011810:Quinoxalines; D011978:Receptors, Nicotinic; D000068580:Varenicline; C426745:5-iodo-3-(2-azetidinylmethoxy)pyridine; C514816:sazetidine-A