title: Ketamine elicits sustained antidepressant-like activity via a serotonin-dependent mechanism.
abstract: BACKGROUND
  Behavioural antidepressant-like effects of ketamine have been reported in the forced swimming test (FST). The mechanisms mediating such effects are unknown.
  
  
  OBJECTIVE
  As serotonin (5-HT) is an important transmitter mediating antidepressant responsiveness in the FST, the influence of 5-HT depletion on the antidepressant-like effect of ketamine was assessed.
  
  
  METHODS
  The effect of ketamine (25 mg/kg, i.p., 1 or 24 h prior to test) was assessed in the FST in naive rats or animals subjected to 5-HT depletion, repeated stress or following a combination of 5-HT depletion and stress. Endogenous 5-HT was depleted using the tryptophan hydroxylase inhibitor para-chlorophenylalanine (3 × 150 mg/kg, i.p.). Stress was induced by physical restraint (2 h/day for 10 days).
  
  
  RESULTS
  In naive rats, ketamine administered 24 or 1 h prior to test produced a characteristic antidepressant-like reduction in immobility time in the FST. Depletion of 5-HT blocked this reduction in immobility when ketamine was administered 24 h prior FST, indicative of 5-HT dependency. The increase in immobility provoked by repeated restraint stress (2 h/day for 10 days) was blocked by ketamine when administered 24 h prior to FST, but this effect dissipated when animals were subjected to 5-HT depletion.
  
  
  CONCLUSIONS
  These observations are consistent with a role for 5-HT in mediating sustained antidepressant activity of ketamine in the FST. Molecular and cellular changes induced by ketamine may produce a rapid adaptation of 5-HT transmission which underlies the antidepressant response.
authors: Neuropsychopharmacology Research Group, School of Pharmacy & Pharmaceutical Sciences and Trinity College Institute of Neuroscience, Trinity College Dublin, Dublin 2, Ireland.
authors: Valentina
authors: V
authors: Gigliucci
authors: Grainne
authors: G
authors: O'Dowd
authors: Sheena
authors: S
authors: Casey
authors: Danielle
authors: D
authors: Egan
authors: Sinead
authors: S
authors: Gibney
authors: Andrew
authors: A
authors: Harkin
mesh_terms: D000818:Animals; D000928:Antidepressive Agents / Q000008:administration & dosage / Q000494:pharmacology*; D003863:Depression / Q000188:drug therapy* / Q000503:physiopathology; D004195:Disease Models, Animal; D018691:Excitatory Amino Acid Antagonists / Q000008:administration & dosage / Q000494:pharmacology; D007649:Ketamine / Q000008:administration & dosage / Q000494:pharmacology*; D008297:Male; D051381:Rats; D017207:Rats, Sprague-Dawley; D012701:Serotonin / Q000378:metabolism*; D013315:Stress, Psychological / Q000188:drug therapy / Q000503:physiopathology; D013550:Swimming; D013997:Time Factors
chemical_list: D000928:Antidepressive Agents; D018691:Excitatory Amino Acid Antagonists; D012701:Serotonin; D007649:Ketamine