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Antidepressant activity of the adenosine A2A receptor antagonist, istradefylline (KW-6002) on learned helplessness in rats.
Psychopharmacology (Berl). 2014 Jul; 231(14):2839-49.P

Abstract

RATIONALE

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.

Authors+Show Affiliations

Development Research Laboratories, Research Division, Kyowa Hakko Kirin Co., Ltd., 1188 Shimotogari, Nagaizumi-cho, Sunto-gun, Shizuoka, 411-8731, Japan.No affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Comparative Study
Journal Article

Language

eng

PubMed ID

24488405

Citation

Yamada, Koji, et al. "Antidepressant Activity of the Adenosine A2A Receptor Antagonist, Istradefylline (KW-6002) On Learned Helplessness in Rats." Psychopharmacology, vol. 231, no. 14, 2014, pp. 2839-49.
Yamada K, Kobayashi M, Shiozaki S, et al. Antidepressant activity of the adenosine A2A receptor antagonist, istradefylline (KW-6002) on learned helplessness in rats. Psychopharmacology (Berl). 2014;231(14):2839-49.
Yamada, K., Kobayashi, M., Shiozaki, S., Ohta, T., Mori, A., Jenner, P., & Kanda, T. (2014). Antidepressant activity of the adenosine A2A receptor antagonist, istradefylline (KW-6002) on learned helplessness in rats. Psychopharmacology, 231(14), 2839-49. https://doi.org/10.1007/s00213-014-3454-0
Yamada K, et al. Antidepressant Activity of the Adenosine A2A Receptor Antagonist, Istradefylline (KW-6002) On Learned Helplessness in Rats. Psychopharmacology (Berl). 2014;231(14):2839-49. PubMed PMID: 24488405.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Antidepressant activity of the adenosine A2A receptor antagonist, istradefylline (KW-6002) on learned helplessness in rats. AU - Yamada,Koji, AU - Kobayashi,Minoru, AU - Shiozaki,Shizuo, AU - Ohta,Teruko, AU - Mori,Akihisa, AU - Jenner,Peter, AU - Kanda,Tomoyuki, Y1 - 2014/02/02/ PY - 2013/06/12/received PY - 2014/01/13/accepted PY - 2014/2/4/entrez PY - 2014/2/4/pubmed PY - 2015/2/11/medline SP - 2839 EP - 49 JF - Psychopharmacology JO - Psychopharmacology (Berl.) VL - 231 IS - 14 N2 - RATIONALE: 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. SN - 1432-2072 UR - https://www.unboundmedicine.com/medline/citation/24488405/Antidepressant_activity_of_the_adenosine_A2A_receptor_antagonist_istradefylline__KW_6002__on_learned_helplessness_in_rats_ L2 - https://dx.doi.org/10.1007/s00213-014-3454-0 DB - PRIME DP - Unbound Medicine ER -