Antidepressant activity of the adenosine A sub(2A) receptor antagonist, istradefylline (KW-6002) on learned helplessness in rats

• Published in: Psychopharmacology 2014-07, Vol.231 (14), p.2839-2849
• Main Authors: Yamada, Koji, Kobayashi, Minoru, Shiozaki, Shizuo, Ohta, Teruko, Mori, Akihisa, Jenner, Peter, Kanda, Tomoyuki
• Format: Article
• Language: English
• ISSN: 0033-3158; 1432-2072
• DOI: 10.1007/s00213-014-3454-0

Rationale: Istradefylline, an adenosine A sub(2A) receptor antagonist, improves motor function in animal models of Parkinson's disease (PD) and in patients with PD. In addition, some A sub(2A) antagonists exert antidepressant-like activity in rodent models of depression, such as the forced swim and the tail suspension tests. Objective: We have investigated the effect of istradefylline on depression-like behaviors using the rat learned helplessness (LH) model. Results: Acute, as well as chronic, oral administration of istradefylline significantly improved the inescapable shock (IES)-induced escape deficit with a degree of efficacy comparable to chronic treatment with the tricyclic antidepressant desipramine and the selective serotonin (5-HT) reuptake inhibitor, fluoxetine. Both the A sub(1)/A sub(2A) receptor nonspecific antagonist theophylline and the moderately selective antagonist CGS15943, but not the A sub(1) selective antagonist DPCPX, ameliorated the IES-induced escape deficit. The enhancement of escape response by istradefylline was reversed by a local injection of the A sub(2A) specific agonist CGS21680 either into the nucleus accumbens, the caudate-putamen, or the paraventricular nucleus of the hypothalamus, but not by the A sub(1) specific agonist R-PIA into the nucleus accumbens. Moreover, neither the 5-HT sub(2A/2C) receptor antagonist methysergide or the adrenergic alpha 2 antagonist yohimbine, nor the beta -adrenergic antagonist propranolol, affected the improvement of escape response induced by istradefylline. Conclusions: Istradefylline exerts antidepressant-like effects via modulation of A sub(2A) receptor activity which is independent of monoaminergic transmission in the brain. Istradefylline may represent a novel treatment option for depression in PD as well as for the motor symptoms.