title: Sildenafil, a phosphodiesterase type 5 inhibitor, reduces antidepressant-like activity of paroxetine in the forced swim test in mice.
abstract: BACKGROUND
  Sildenafil, a selective phosphodiesterase 5 (PDE5) inhibitor, has recently been reported to influence the antidepressant activity of some antidepressant drugs. The present study was undertaken to investigate the involvement of the nitric oxide/cyclic guanosine 3',5'-monophosphate/PDE5 (NO/cGMP/PDE5) signaling pathway in the antidepressant activity of paroxetine and to assess the interaction between paroxetine and sildenafil, in the forced swim test in mice.
  
  
  METHODS
  Swim trials were conducted by placing mice in glass cylinders filled with water for 6 min. Total behavioral immobility was measured during the last 4 min of the test. Changes in locomotor activity were measured with photoresistor actimeters. Serum and brain paroxetine concentrations were assayed by the HPLC method.
  
  
  RESULTS
  Paroxetine at a dose of 1 mg/kg significantly decreased immobility time in the forced swim test, while sildenafil (5, 10 and 20 mg/kg) in a dose-dependent manner reduced the antidepressant activity of paroxetine. Pharmacokinetic studies did not show any significant changes in paroxetine concentration in serum and brain tissue as compared to paroxetine treatment alone.
  
  
  CONCLUSIONS
  The results suggest that paroxetine may exert its antidepressant action by decreasing cGMP levels and sildenafil, as a drug which has the opposite effect on the processes mediated via the NO/cGMP/PDE5 signaling pathway, may decrease the efficacy of paroxetine. However, the co-administration of paroxetine with sildenafil resulted in a potent reduction (80%) of locomotor activity, which suggests that the reversal of antidepressant action of paroxetine may have been a result of locomotor deficits. Further studies are required to explain the mechanism underlying this phenomenon.
authors.affiliation: Department of Animal Physiology, Faculty of Biology and Biotechnology, Maria Curie-Skłodowska University, Akademicka 19, PL 20-033 Lublin, Poland.
authors.forename: Katarzyna
authors.initials: K
authors.lastname: Socała
authors.forename: Dorota
authors.initials: D
authors.lastname: Nieoczym
authors.forename: Elżbieta
authors.initials: E
authors.lastname: Wyska
authors.forename: Ewa
authors.initials: E
authors.lastname: Poleszak
authors.forename: Piotr
authors.initials: P
authors.lastname: Wlaź
mesh_terms: D000818:Animals; D000928:Antidepressive Agents / Q000494:pharmacology*; D001921:Brain / Q000378:metabolism; D002118:Calcium / Q000378:metabolism; D006152:Cyclic GMP / Q000502:physiology; D008297:Male; D051379:Mice; D009043:Motor Activity / Q000187:drug effects; D019001:Nitric Oxide Synthase / Q000037:antagonists & inhibitors; D017374:Paroxetine / Q000493:pharmacokinetics / Q000494:pharmacology*; D058986:Phosphodiesterase 5 Inhibitors / Q000494:pharmacology*; D010879:Piperazines / Q000494:pharmacology*; D011687:Purines / Q000494:pharmacology; D000068677:Sildenafil Citrate; D013450:Sulfones / Q000494:pharmacology*; D013550:Swimming
chemical_list: D000928:Antidepressive Agents; D058986:Phosphodiesterase 5 Inhibitors; D010879:Piperazines; D011687:Purines; D013450:Sulfones; D017374:Paroxetine; D000068677:Sildenafil Citrate; D019001:Nitric Oxide Synthase; D006152:Cyclic GMP; D002118:Calcium