Antidepressant activity of the adenosine [A.sub.2A] receptor antagonist, istradefylline on learned helplessness in rats

• Published in: Psychopharmacology Vol. 231; no. 14; p. 2839
• Main Authors: Yamada, Koji, Kobayashi, Minoru, Shiozaki, Shizuo, Ohta, Teruko, Mori, Akihisa, Jenner, Peter, Kanda, Tomoyuki
• Format: Journal Article
• Language: English
• Published: Springer 15-07-2014
• Subjects: Antidepressants; Complications and side effects; Depression, Mental; Dosage and administration; Drug therapy; Japan
• ISSN: 0033-3158
• 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 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 [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. Keywords Adenosine [A.sub.2A] receptor * Istradefylline * KW-6002 * Parkinson's disease * Antidepressant * Learned helplessness * Behavior