title: Antidepressant-like activity of the adenosine A(2A) receptor antagonist, istradefylline (KW-6002), in the forced swim test and the tail suspension test in rodents.
abstract: BACKGROUND
  Depression is common in Parkinson's disease (PD) but its response to classical antidepressants is not clear. The adenosine A2A antagonist istradefylline is effective in the treatment of the motor symptoms of PD but inhibition of the adenosine A2A receptor may also induce antidepressant-like effects.
  
  
  OBJECTIVE
  We have investigated whether istradefylline might be effective in treating depression in PD using the forced swimming test (FST) and the tail suspension test (TST) in rodents.
  
  
  RESULTS
  Istradefylline significantly decreased immobility time in the FST in both rats and mice (0.16mg/kg and higher) with comparable efficacy to an equivalent dose of the tricyclic antidepressants, desipramine and imipramine. Both 8-OH-DPAT (5-HT1A agonist) and quinpirole (D2 agonist) also reduced the immobility time. The istradefylline-induced reduction of immobility time was attenuated by corticosterone. In addition, the combined use of a sub-threshold dose of istradefylline and the serotonin-noradrenaline reuptake inhibitor venlafaxine ameliorated depression-like behavior in the mouse FST. In the mouse TST, istradefylline (0.08mg/kg and higher) decreased immobility time. Moreover, co-administration of istradefylline with paroxetine or fluoxetine (selective serotonin reuptake inhibitors) or deprenyl (MAO-B inhibitor) at doses that did not show antidepressant-like effects when administered alone, resulted in a significant reduction in immobility time.
  
  
  CONCLUSIONS
  Istradefylline alone or co-administered with currently available antidepressants, may be useful for the treatment of depression as well as motor symptoms of PD. Its effects might be, at least in part, attributable to modulation of hypothalamic-pituitary-adrenal axis.
authors.affiliation: Development Research Laboratories, Research Division, Kyowa Hakko Kirin Co., Ltd., Shizuoka, Japan.
authors.forename: Koji
authors.initials: K
authors.lastname: Yamada
authors.forename: Minoru
authors.initials: M
authors.lastname: Kobayashi
authors.forename: Akihisa
authors.initials: A
authors.lastname: Mori
authors.forename: Peter
authors.initials: P
authors.lastname: Jenner
authors.forename: Tomoyuki
authors.initials: T
authors.lastname: Kanda
mesh_terms: D058917:Adenosine A2 Receptor Antagonists / Q000494:pharmacology*; D000818:Animals; D008297:Male; D051379:Mice; D011687:Purines / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D013312:Stress, Physiological; D013550:Swimming
chemical_list: D058917:Adenosine A2 Receptor Antagonists; D011687:Purines; C111599:istradefylline
keywords: 5-HT; 5-hydroxytryptamine; 50% effective dose; 8-OH-DPAT; 8-hydroxy-2-(dipropylamino)tetralin; ACTH; Adenosine A(2A) receptor; Antidepressant; COMT; ED(50); FST; Forced swimming test; HPA; Istradefylline; KW-6002; MAO; MED; PD; Parkinson's disease; SNRI; SSRI; TCA; TST; Tail suspension test; adrenocorticotropic hormone; catecholamine-O-methyltransferase; forced swim test; hypothalamic–pituitary–adrenal; minimum effective dose; monoamine oxidase; serotonin noradrenaline reuptake inhibitor; serotonin-noradrenaline reuptake inhibitor; tail suspension test; tricyclic antidepressant