title: Antidepressant-like effects of guanfacine and sex-specific differences in effects on c-fos immunoreactivity and paired-pulse ratio in male and female mice.
abstract: BACKGROUND
  The a2A-noradrenergic agonist guanfacine can decreases stress-induced smoking in female, but not male, human smokers. It is not known whether these effects are due to effects on mood regulation and/or result from nicotinic-cholinergic interactions.
  
  
  OBJECTIVE
  The objective of the study was to determine whether there are sex differences in the effect of guanfacine in tests of anxiolytic and antidepressant efficacy in mice at baseline and in a hypercholinergic model of depression induced by the acetylcholinesterase inhibitor physostigmine.
  
  
  METHODS
  The effects of guanfacine were measured in the light/dark box, tail suspension, and the forced swim test in female and male C57BL/6J mice. In parallel, electrophysiological properties were evaluated in the prefrontal cortex, a critical brain region involved in stress responses. c-fos immunoreactivity was measured in other brain regions known to regulate mood.
  
  
  RESULTS
  Despite a baseline sex difference in behavior in the forced swim test (female mice were more immobile), guanfacine had similar, dose-dependent, antidepressant-like effects in mice of both sexes (optimal dose, 0.15 mg/kg). An antidepressant-like effect of guanfacine was also observed following pre-treatment with physostigmine. A sex difference in the paired-pulse ratio in the prefrontal cortex (PFC) (male, 1.4; female, 2.1) was observed at baseline that was normalized by guanfacine. Other brain areas involved in cholinergic control of depression-like behaviors, including the basolateral amygdala and lateral septum, showed sex-specific changes in c-fos expression.
  
  
  CONCLUSIONS
  Guanfacine has a robust antidepressant-like effect and can reverse a depression-like state induced by increased acetylcholine (ACh) signaling. These data suggest that different brain areas are recruited in female and male mice, despite similar behavioral responses to guanfacine.
authors.affiliation: Department of Psychiatry, Yale University School of Medicine, 34 Park Street-3rd floor research, New Haven, CT, 06508, USA.
authors.forename: Yann S
authors.initials: YS
authors.lastname: Mineur
authors.forename: Matthew P
authors.initials: MP
authors.lastname: Bentham
authors.forename: Wen-Liang
authors.initials: WL
authors.lastname: Zhou
authors.forename: Margreet E
authors.initials: ME
authors.lastname: Plantenga
authors.forename: Sherry A
authors.initials: SA
authors.lastname: McKee
authors.forename: Marina R
authors.initials: MR
authors.lastname: Picciotto
mesh_terms: D000818:Animals; D000928:Antidepressive Agents / Q000494:pharmacology / Q000627:therapeutic use*; D001921:Brain / Q000187:drug effects / Q000378:metabolism*; D003863:Depression / Q000188:drug therapy* / Q000378:metabolism* / Q000523:psychology; D005260:Female; D016316:Guanfacine / Q000494:pharmacology / Q000627:therapeutic use*; D006339:Heart Rate / Q000187:drug effects / Q000502:physiology; D019417:Hindlimb Suspension; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D017397:Prefrontal Cortex / Q000187:drug effects / Q000378:metabolism; D016760:Proto-Oncogene Proteins c-fos / Q000096:biosynthesis*; D012727:Sex Characteristics; D013550:Swimming / Q000502:physiology / Q000523:psychology; D016896:Treatment Outcome
chemical_list: D000928:Antidepressive Agents; D016760:Proto-Oncogene Proteins c-fos; D016316:Guanfacine