Antidepressant activity of the adenosine A2A receptor antagonist, istradefylline (KW-6002) on learned helplessness in rats.
BACKGROUND
Istradefylline, an adenosine A2A receptor antagonist, improves motor function in animal models of Parkinson's disease (PD) and in patients with PD. In addition, some A2A 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 A1/A2A receptor nonspecific antagonist theophylline and the moderately selective antagonist CGS15943, but not the A1 selective antagonist DPCPX, ameliorated the IES-induced escape deficit. The enhancement of escape response by istradefylline was reversed by a local injection of the A2A specific agonist CGS21680 either into the nucleus accumbens, the caudate-putamen, or the paraventricular nucleus of the hypothalamus, but not by the A1 specific agonist R-PIA into the nucleus accumbens. Moreover, neither the 5-HT2A/2C receptor antagonist methysergide or the adrenergic α 2 antagonist yohimbine, nor the β-adrenergic antagonist propranolol, affected the improvement of escape response induced by istradefylline.


CONCLUSIONS
Istradefylline exerts antidepressant-like effects via modulation of A2A 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.
Development Research Laboratories, Research Division, Kyowa Hakko Kirin Co., Ltd., 1188 Shimotogari, Nagaizumi-cho, Sunto-gun, Shizuoka, 411-8731, Japan.
Koji
K
Yamada
Minoru
M
Kobayashi
Shizuo
S
Shiozaki
Teruko
T
Ohta
Akihisa
A
Mori
Peter
P
Jenner
Tomoyuki
T
Kanda
D058917:Adenosine A2 Receptor Antagonists / Q000494:pharmacology*; D000818:Animals; D000928:Antidepressive Agents / Q000494:pharmacology*; D001522:Behavior, Animal / Q000187:drug effects; D001921:Brain / Q000187:drug effects / Q000378:metabolism; D003863:Depression / Q000188:drug therapy*; D003891:Desipramine / Q000494:pharmacology; D004195:Disease Models, Animal; D004924:Escape Reaction / Q000187:drug effects; D005467:Floxuridine / Q000494:pharmacology; D006380:Helplessness, Learned; D019417:Hindlimb Suspension; D008297:Male; D010300:Parkinson Disease / Q000188:drug therapy / Q000503:physiopathology; D011687:Purines / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D013550:Swimming
D058917:Adenosine A2 Receptor Antagonists; D000928:Antidepressive Agents; D011687:Purines; D005467:Floxuridine; C111599:istradefylline; D003891:Desipramine