title: Effects of acute and repeated dose administration of caffeine and pentoxifylline on diazepam-induced mouse behavior in the hole-board test.
abstract: BACKGROUND
  The behavioral effects of methyl xanthines and their interactions with benzodiazepines have not been clearly established in animal models of anxiety.
  
  
  OBJECTIVE
  The present study extended the previous studies to determine the effects of acute and repeated administration of caffeine, a non-specific phosphodiesterase (PDE) inhibitor and pentoxyfylline, a specific type-4 phosphodiesterase (PDE4) inhibitor on (1) baseline anxiety-like behavior and (2) the response to an acute challenge with diazepam on anxiety-like behavior in the hole-board test.
  
  
  METHODS
  Mice were observed for the number of head-dips they made into the holes of the hole-board apparatus during a 5-min period, starting 30 min after acute (20 mg/kg) and repeated oral dose (20 mg/kg, twice a day for 4 days) administration of caffeine and pentoxifylline. In separate experiments, the response to an acute challenge with graded doses of diazepam (0.375 3 mg/kg, SC) was observed in naive mice or mice on acute and repeated dose regimen with methyl xanthines.
  
  
  RESULTS
  Mice on acute but not after repeated dose regimen demonstrated a significantly increased number of hole-dips, indicating an anxiolytic-like effect of methylxanthines. Diazepam at the lower doses (0.375 and 0.75 mg/kg) but not at the highest doses (1.5 and 3 mg/kg) examined produced a significant anxiolytic-like effect. After an acute dose exposure of mice to caffeine and pentoxifylline, a rightward shift in the dose-response curve of diazepam was observed and particularly at 1.5 mg/kg dose, the net effect of diazepam was significantly enhanced which was, however, impaired upon repeated administration, more so with caffeine than with pentoxifylline.
  
  
  CONCLUSIONS
  It is concluded that the xanthine drugs exert anxiolytic-like activity similar to diazepam in the hole-board test. In addition, they seem to modulate the anxiolytic effects of diazepam after both acute and repeated administration, probably as a result of an endogenous adenosinergic mechanism which may have therapeutic significance.
authors.affiliation: Department of Physiology and Pharmacology, Faculty of Medicine, Federal University of Ceará, Fortaleza, Brazil. vsnrao@hotmail.com
authors.forename: V S
authors.initials: VS
authors.lastname: Rao
authors.forename: F A
authors.initials: FA
authors.lastname: Santos
authors.forename: W G
authors.initials: WG
authors.lastname: Paula
authors.forename: R M
authors.initials: RM
authors.lastname: Silva
authors.forename: A R
authors.initials: AR
authors.lastname: Campos
mesh_terms: D000704:Analysis of Variance; D000818:Animals; D001007:Anxiety / Q000503:physiopathology*; D001522:Behavior, Animal / Q000187:drug effects*; D002110:Caffeine / Q000008:administration & dosage*; D003975:Diazepam / Q000494:pharmacology*; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D008297:Male; D051379:Mice; D010431:Pentoxifylline / Q000008:administration & dosage*
chemical_list: D002110:Caffeine; D003975:Diazepam; D010431:Pentoxifylline