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. 2020 Mar 31;16(2):167–174. doi: 10.1007/s11302-020-09694-2

The belated US FDA approval of the adenosine A2A receptor antagonist istradefylline for treatment of Parkinson’s disease

Jiang-Fan Chen 1,✉, Rodrigo A Cunha 2
PMCID: PMC7367999  PMID: 32236790

Abstract

After more than two decades of preclinical and clinical studies, on August 27, 2019, the US Food and Drug Administration (FDA) approved the adenosine A2A receptor antagonist Nourianz® (istradefylline) developed by Kyowa Hakko Kirin Inc., Japan, as an add-on treatment to levodopa in Parkinson’s disease (PD) with “OFF” episodes. This milestone achievement is the culmination of the decade-long clinical studies of the effects of istradefylline in more than 4000 PD patients. Istradefylline is the first non-dopaminergic drug approved by FDA for PD in the last two decades. This approval also provides some important lessons to be remembered, namely, concerning disease-specific adenosine signaling and targeting subpopulation of PD patients. Importantly, this approval paves the way to foster entirely novel therapeutic opportunities for adenosine A2A receptor antagonists, such as neuroprotection or reversal of mood and cognitive deficits in PD and other neuropsychiatric diseases.

Keywords: Adenosine, A2A receptor, Parkinson’s disease, istradefylline, KW6002, clinical trial, safety, therapy

Adenosine A2A receptors in Parkinson’s disease: preclinical basis

Motor deficits characteristic of PD involve an over-activation of the striatopallidal pathway of the dorsal striatum due to a lack of dopamine signaling, which is the main brake of this pathway [75]. Notably, adenosine A2A receptors (A2AR) have a strikingly high density in dopamine D2 receptor (D2R)-containing striatopallidal neurons in rodents, non-human primates and humans. A2AR agonists inhibit striatal D2R binding, D2R-mediated neurotransmitter release and immediate early gene expression [25], possibly through A2AR-D2R heteromers [7]. This unique co-localization and antagonistic interaction between A2AR and D2R in striatopallidal neurons together with the ability of A2AR to control glutamatergic terminals driving striatal circuits [67] provide a strong anatomical and molecular basis for striatal A2AR to integrate dopamine and glutamate signals [70] modulating striatal synaptic plasticity [20, 26], thus justifying the motor and possibly cognitive benefits of A2AR antagonists in PD [69, 70].

Since the 1980s, medicinal chemistry has generated antagonists with high affinity (KD of low nM) and selectivity (> 100–200-fold over other adenosine receptor subtypes) for the human variants of the A2AR [55]. Several A2AR antagonists with largely different core structures (see Fig. 1) including istradefylline, preladenant and tozadenant were developed and tested in preclinical and clinical studies for the treatment of PD [36]. Indeed, since the early 1990s, mounting experimental findings have demonstrated the motor enhancement effect of A2AR antagonists, alone or synergizing with L-DOPA and D2R agonists, in rodents [63] and non-human primates [38] by acting at striatopallidal A2AR. These preclinical studies have confirmed the validity of A2AR as a novel target for PD treatment and prompted the clinical studies as a leading non-dopaminergic therapeutic target in PD.

Fig. 1.

Fig. 1

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Chemical structures of different antagonists of adenosine A2A receptors tested in humans

Clinical development of A2AR antagonists

Several A2AR antagonists have been developed and tested in humans. Overall, since 2001, more than 25 clinical trials were conducted to evaluate the safety and clinical efficacy of A2AR antagonists in PD patients; among these, eight double-blind, placebo-controlled, phase IIb and III trials of istradefylline (KW-6002, > 4000 PD patients), one phase IIb trial with preladenant (SCH 420814, 253 PD patients) and one phase IIb trial with tozadenant (337 PD patients) all reported motor benefits in advanced PD patients as an add-on therapy with L-DOPA [4, 31, 32, 40]. There is a single report of another A2AR antagonist vipadenant, which only shows the occupation between 74 and 94% of A2AR in human brain regions (including putamen) at a dose of 2.5 mg (saturation obtained at 100 mg) and no description of effects in PD patients [5].

Istradefylline is a xanthine derivative developed by Kyowa Hakko Kirin Inc., with a relatively high affinity for A2AR (KD = 10–20 nM) and selectivity towards A1R (100 times selective), when compared with preladenant (SCH 420814) first developed by Schering-Plough Corp. and then acquired by Merck & Co Inc., which has a higher affinity (KD of 0.9 nM) and a higher selectivity for A2AR (1000 times versus A1R). Preladenant belongs to a different chemical family and has a larger molecular weight than istradefylline, which may become a liability due to a more limited bioavailability. Furthermore, pharmacokinetic studies of preladenant in human volunteers reported a moderate to high coefficient of variation across different doses [19]. In fact, despite some positive results in an initial phase IIb trial with long-term treatment with preladenant (5–10 mg/kg, twice a day) [23, 31], two subsequent phase III trials failed to show the clinical efficacy of preladenant to significantly decrease “OFF” time compared with placebo either in conjunction with L-DOPA treatment [33] or in monotherapy [74]. However, this conclusion is blurred by the parallel lack of efficacy of the active control rasagiline, suggesting that issues of study design may have affected these particular trials that lead to the suspension of the preladenant program by Merck & Co Inc.

Long history of istradefylline development

The detailed description of the clinical trials with istradefylline has been provided in several previous reviews [14, 42, 60, 79, 83] and meta-analyses [66]. These clinical IIb and III trials involving a total of > 4000 PD patients [including studies in Japan [44, 53, 54], in North America in 2003–2007 [30, 46, 73], one study in North America in 2016 (NCT02610231) and one study in Europe], showed a relatively modest but significant motor benefit, namely, a reduction of the average “OFF” time by ~ 1.7 h compared to the “optimal” L-DOPA dose regimen [36]. However, the US FDA initially considered in 2008 that this modest motor benefit was not sufficient to support the clinical utility of istradefylline for PD. To address this efficacy issue, additional PD clinical trials with istradefylline in Japan were undertaken to show consistent motor benefits, leading to the approval of istradefylline for treatment of PD in Japan in March 2013 [22]. Additionally, an interim analysis of a post-marketing surveillance study in Japan with 476 PD patients showed that istradefylline effectively reduces “OFF” time symptoms and improves motor dysfunction in 44.7% and 48.5% of patients, with a mean decrease of the UPDRS Part III score from 33.7 to 30.3 at the end of the study and a physician’s global assessment of drug as effective in 61.3% of patients [76]. Furthermore, a single-arm, open-label, prospective, multicentre study also showed that istradefylline treatment improves gait deficits and sleepiness in PD patients [35, 51] and corrects postural deformities in a small number of PD patients [27].

Finally, after reviewing the data from 5 pivotal clinical trials (including 3 phase III and 2 phase IIb trials, all using as the primary endpoint the change in the subjects’ percentage of their daily awake time spent in the “OFF” state and the PD patient diary as the primary data), the US FDA considered istradefylline to be effective selectively for PD with “OFF” episodes (total 1143 PD participants with “OFF” episodes) as an add-on treatment to L-DOPA/carbidopa. As a result, on August 27, 2019, the US FDA has granted approval for Nourianz® (istradefylline) to be used as adjunctive treatment to L-DOPA in adult patients with PD experiencing “OFF” episodes (see https://www.kyowakirin.com/media_center/news_releases/2016/e20161213_01.html). This is an important milestone in PD drug development, providing PD patients with a novel non-dopaminergic once-a-day oral treatment option in conjunction with L-DOPA for PD.

Safety profile of A2AR antagonists

Notably, these clinical IIb and III trials with istradefylline showed a very consistent safety profile in > 4000 advanced PD patients [31, 37]. The most common adverse reactions for patients taking istradefylline are non-troublesome dyskinesia, dizziness, constipation, nausea, hallucination and insomnia. The post-market surveillance study similarly showed that long-term treatment with istradefylline in a real-world setting for PD patients is generally well tolerated, with the most common adverse reactions being dyskinesia and hallucination [76]. Importantly, potential side effects related to different biological roles of A2AR, such as the control of the immune-inflammatory system [72], sleep [45] and vascular tone [71], are not evident in clinical trials, which noted the absence of insomnia, hypertension or increased infection rates [31, 37, 76]. This general lack of side effects of istradefylline is entirely consistent with the general safety associated with the widespread use of the non-selective adenosine receptor antagonist caffeine in moderate doses in 70% of the human population, with striking benefits of increasing healthspan on ageing [41].

This safe profile of istradefylline is in sharp contrast to the recent report that tozadenant (an A2AR antagonist from a different chemical class of istradefylline) has unfortunately resulted in the death of 5 patients in a clinical phase III trial involving 409 participants [10]. The causes of death were identified as drug-induced agranulocytosis, a process resulting from drug- or hapten-induced formation of antibodies against neutrophil membrane glycoproteins, leading to neutrophil destruction. This was never observed with istradefylline but has been reported to occur for multiple other drugs such as dipyrone, diclofenac, calcium dobesilate, spironolactone, carbamazepine, clozapine, sulfamethoxazole, trimethoprim, antithyroid drugs or β-lactam antibiotics. Thus, additional experiments are required to determine if the complications associated with tozadenant are either related to its particular chemical structure or might instead involve A2AR.

Lessons learned from istradefylline drug development

This long history of istradefylline development offers several important lessons for future adenosine-related and PD-related drug development. As noted above, a large number of phase IIb–III trials have demonstrated that istradefylline affords relatively mild motor benefits but with noted safety profile. It is surprising that these fundamental clinical features desired for any drug (efficacy, even if moderate, and safety) were not valued to merit US FDA approval. In fact, the initial submission (in 2007) of istradefylline targeting the entire PD population in 5 studies involving a total ~ 3500 patients was unsuccessful. This US FDA decision for this disapproval was largely based on the opinion that “the efficacy data of istradefylline was not sufficient to support its clinical utility”. The final submission in 2018 selected 1134 patients from the total 4000 participants from all 7 phase III trials with istradefylline: the selection of only PD patients with “OFF” episodes allowed to highlight the clinical efficacy of istradefylline, thus leading to the approval of istradefylline by US FDA. The critical difference between these two submissions is the selection of only 1134 PD patients with “OFF” episodes to better highlight the clinical efficacy of istradefylline. This shows, once again, that the selection of specific patient subpopulations who are most responsive to the tested drug is critical for a successful demonstration of the clinical efficacy of a drug. Additional factors contributing to this substantially delayed approval by the US FDA include regulatory delays, corporate mergers (Kyowa Hakko Kogyo is now Kyowa Hakko Kirin) and formulation issues related to the fact that KW-6002 can isomerize in solution when exposed to light.

As the main pharmacological targets of caffeine are adenosine receptors, particularly A2AR as revealed by genetic knockout studies [50, 81], it is highly possible that a different pattern of caffeine consumption in human populations may affect their response to drugs targeting adenosine receptor due to their pharmacokinetic and pharmacodynamic (PK/PD) interaction with caffeine. Indeed, PK/PD analysis shows that caffeine ingestion at a dose equivalent to regular human consumption (2–4 cups of coffee) can affect A2AR agonist-induced myocardial perfusion imaging [77] and reduces the efficacy of adenosine in the treatment of paroxysmal supraventricular tachycardia [6]. Thus, it is somewhat surprising that several clinical phase III trials with A2AR antagonists in advanced PD patients apparently did not consider monitoring and recording the consumption of caffeine [24, 30–33, 40, 44, 46, 51, 73]. We proposed [14] that sufficient information on caffeine intake should always be incorporated into any clinical trial of A2AR-based therapies.

Development of next generation of A2AR antagonists

As the patent life of istradefylline is coming to an end (expected in 2024, with a new formulation), Kyowa Hakko Kirin has strategically developed a second generation of A2AR antagonists, namely, KW-6356, which has a longer patent life (https://www.kyowakirin.com/media_center/news_releases/2018/e20180820_01.html). However, very limited information is available on the pharmacological profile of KW-6356, with regard to its affinity and selectivity for A2AR or its pharmacokinetics. It has only been publicized that a multicentre, randomized, double-blind, placebo-controlled, phase IIb study involving 168 participants (NCT03703570) is ongoing to evaluate the effect of KW-6356 on motor symptoms in PD. Interestingly, a monotherapy for de novo PD patients is being pursued with KW-6356, and it was reported that both a low and a high dose of KW-6356 reduce motor dysfunction scores compared with placebo (NCT02939391). Thus, KW-6356 monotherapy is apparently well tolerated (no major safety issues were observed) and effective in the treatment of motor symptoms in early/de novo PD patients.

Novel prospects offered by istradefylline approval for PD treatment

Neuroprotective effects of A2AR antagonists in PD

Since 2000, at least five large prospective studies, initially from the Honolulu Heart Program [64], followed by the Health Professionals Follow-Up Study and the Nurses’ Health Study – involving 47,351 men and 88,565 women [3], by the Finnish Mobile Clinic Health Examination Survey [65] and by the NeuroGenetics Research Consortium [62], have firmly established a relationship between increased caffeine consumption and a decreased risk of developing PD [2]. The neuroprotective potential of caffeine and A2AR antagonists (reviewed in [17]) is further substantiated by animal studies demonstrating a neuroprotective effect of both the pharmacological and genetic blockade of A2AR in animal models of PD [13, 38] as well as stroke [12], traumatic brain injury [47], epilepsy [9], spinocerebellar ataxia [28] or Alzheimer’s disease [8]. However, the lack of sensitive biomarkers for PD progression and the lack of proper clinical trial designs to uncover neuroprotective effects in the face of the slow progression of PD and relatively short (usually < 52 weeks) clinical trial periods have hindered testing this critically important issue. With the US FDA approval of istradefylline, phase IV clinical studies of istradefylline in PD patients will allow long-term monitoring of the disease course to evaluate possible neuroprotective effects of istradefylline on PD progression.

Pro-cognitive effects of A2AR antagonists in PD

PD is primarily characterized by cardinal motor symptoms, but cognitive dysfunction also occurs both in the early and later stages of the disease process [11]: ~ 30% of PD patients have dementia, and an additional 25% of non-demented PD patients develop mild cognitive impairments that are characterized by fronto-striatal cognitive deficits such as alterations in executive function, attention, working and episodic memory. These early cognitive deficits are particularly troubling to patients and reduce their quality of life. Currently, there is no effective treatment for mild cognitive impairments in PD. Recent preclinical studies in rodents and non-human primates demonstrated that A2AR antagonists not only enhance working memory [84], reversal learning [59], set-shifting [52], goal-directed behaviour [49] and Pavlovian conditioning [80] in normal animals but also reverse working memory impairments in animal models of PD [43] and Huntington’s disease [48], traumatic brain injury [57] as well as Alzheimer’s disease [21]. Thus, A2AR may represent a novel therapeutic target for improving cognitive impairments in PD, as heralded by the improvement of cognitive performance by caffeine in PD patients [15]. However, the effect of istradefylline on cognition was not considered in the clinical trials testing A2AR antagonists in PD patients. With the approval of istradefylline, it will now be possible to evaluate the ability of A2AR antagonists to reverse cognitive deficits in PD patients in clinical phase IV trials.

Mood normalizing effects of A2AR antagonists in PD

PD patients often display mood-related alterations [68], typified by the occurrence of anxiety and depressive-like disorders in ~ 40% of patients since early stages of the disease [78]. A2AR function impacts on several psychiatric symptoms [18] with A2AR over-activation bolstering anxiety and depressive-like behaviour [16] and A2AR blockade preventing and reverting repeated stress-induced depressive-like behaviour in rodents [39]. Furthermore, A2AR polymorphisms are correlated with the incidence of anxiety [34] and depression [58]. Notably, recent studies in PD patients showed that caffeine intake reduces the severity of the mood domains in the Mini-Mental State Examination [15] and istradefylline improves the scores of Snaith-Hamilton Pleasure Scale Japanese (SHAPS-J) version, of the Apathy scale and of the Beck Depression Inventory independently of its effects on motor symptoms [56]. The approval of istradefylline will now allow detailing in phase IV clinical trials the expected benefits of A2AR antagonists on different psychiatric symptoms afflicting PD patients.

Opportunities to develop personalized treatments with A2AR antagonist, based on caffeine genetics

Selecting the population of patients for clinical trials is always critical to a successful outcome of the trials. This includes selecting homogenous populations of PD patients who are most responsive to the treatment with A2AR antagonists, according not only to specific clinical features (such as with defined “OFF” episodes) but also to genetic variability (i.e. single nucleotide polymorphisms) of A2AR. The genetic studies related to caffeine sensitivity offer a unique opportunity for “personalized medicine” by identifying useful pharmacogenetic markers for predicting individual responses to caffeine in PD populations in clinical trials. During the last two decades, many genetic studies have been carried out to determine a possible genetic basis for the known human individual variation in caffeine response [82]. Genome-wide association and interaction studies have revealed associations between: (i) an Adora2a variant (rs7165183and rs5996696) and a reduced risk of PD [61]; (ii) a stronger coffee-PD association and slow metabolizers of caffeine with homozygous carriers of the CYP1A2 polymorphisms [1]; and (iii) polymorphism rs4998386 and neighbouring SNPs in GRIN2A and heavy coffee drinkers with the reduced risk of developing PD [29]. As caffeine and A2AR antagonists share a common target and elimination mechanisms, these findings raise the exciting possibility of predicting individual responses to caffeine (and possibly other adenosine receptor antagonists) and selection of patient subpopulations by caffeine genetic polymorphisms of these associated alleles identified (such as CYP1A1, CYP1A2, Adora2a, NRCAM and GRIN2A).

Concluding remarks

The US FDA approval on August 2019 of the A2AR antagonist istradefylline (Nourianz®) as an add-on treatment to levodopa in PD patients with “OFF” episodes is a milestone achievement in adenosine research and PD drug development; in fact, istradefylline is the first A2AR therapeutic drug and the first non-dopaminergic drug approved by US FDA in the last two decades for PD treatment. While multiple factors contributed to substantially delay US FDA approval, the important lessons learned from this belated approval is that the selection of defined patient subpopulations who are most responsive to the tested drug is critical for a successful demonstration of the clinical efficacy of the drug. Importantly, this approval opens new avenues to foster entirely novel therapeutic opportunities for A2AR antagonists, such as neuroprotection and reversal of mood and cognitive deficits in PD.

Funding information

JFC is supported by National Natural Science Foundation of China grant (n° 96018002, n° 80217011, n° 80216083); start-up Fund from Wenzhou Medical University (n° 89212012); RAC is supported by Fundacion LaCaixa (HR17-00523), Centro 2020 (CENTRO-01-0145-FEDER-000008: BrainHealth 2020 and CENTRO-01-0246-FEDER-000010) and FCT (POCI-01-0145-FEDER-03127).

Compliance with ethical standards

Conflict of Interest

Dr. Jiang-Fan Chen declared no conflict of interest.

Competing interests

R.A. Cunha is a scientific consultant to ISIC – Institute for Scientific Information on Coffee.

Ethical approval

This article does not contain any studies with participants or animals performed by either of the authors.

Footnotes

Publisher’s note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

References

  • 1.Amin N, Byrne E, Johnson J, Chenevix-Trench G, Walter S, Nolte IM, kConFab Investigators. Vink JM, Rawal R, Mangino M, Teumer A, Keers JC, Verwoert G, Baumeister S, Biffar R, Petersmann A, Dahmen N, Doering A, Isaacs A, Broer L, Wray NR, Montgomery GW, Levy D, Psaty BM, Gudnason V, Chakravarti A, Sulem P, Gudbjartsson DF, Kiemeney LA, Thorsteinsdottir U, Stefansson K, van Rooij FJ, Aulchenko YS, Hottenga JJ, Rivadeneira FR, Hofman A, Uitterlinden AG, Hammond CJ, Shin SY, Ikram A, Witteman JC, Janssens AC, Snieder H, Tiemeier H, Wolfenbuttel BH, Oostra BA, Heath AC, Wichmann E, Spector TD, Grabe HJ, Boomsma DI, Martin NG, van Duijn CM. Genome-wide association analysis of coffee drinking suggests association with CYP1A1/CYP1A2 and NRCAM. Mol Psychiatry. 2012;17:1116–1129. doi: 10.1038/mp.2011.101. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 2.Ascherio A, Schwarzschild MA. The epidemiology of Parkinson's disease: risk factors and prevention. Lancet Neurol. 2016;15:1257–1272. doi: 10.1016/S1474-4422(16)30230-7. [DOI] [PubMed] [Google Scholar]
  • 3.Ascherio A, Zhang SM, Hernán MA, Kawachi I, Colditz GA, Speizer FE, Willett WC. Prospective study of caffeine consumption and risk of Parkinson's disease in men and women. Ann Neurol. 2001;50:56–63. doi: 10.1002/ana.1052. [DOI] [PubMed] [Google Scholar]
  • 4.Barkhoudarian MT, Schwarzschild MA. Preclinical jockeying on the translational track of adenosine A2A receptors. Exp Neurol. 2011;228:160–164. doi: 10.1016/j.expneurol.2010.12.022. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 5.Brooks DJ, Papapetropoulos S, Vandenhende F, Tomic D, He P, Coppell A, O'Neill G. An open-label, positron emission tomography study to assess adenosine A2A brain receptor occupancy of vipadenant (BIIB014) at steady-state levels in healthy male volunteers. Clin Neuropharmacol. 2010;33:55–60. doi: 10.1097/WNF.0b013e3181d137d2. [DOI] [PubMed] [Google Scholar]
  • 6.Cabalag MS, Taylor DM, Knott JC, Buntine P, Smit D, Meyer A. Recent caffeine ingestion reduces adenosine efficacy in the treatment of paroxysmal supraventricular tachycardia. Acad Emerg Med. 2010;17:44–49. doi: 10.1111/j.1553-2712.2009.00616.x. [DOI] [PubMed] [Google Scholar]
  • 7.Canals M, Marcellino D, Fanelli F, Ciruela F, de Benedetti P, Goldberg SR, Neve K, Fuxe K, Agnati LF, Woods AS, Ferré S, Lluis C, Bouvier M, Franco R. Adenosine A2A-dopamine D2 receptor-receptor heteromerization: qualitative and quantitative assessment by fluorescence and bioluminescence energy transfer. J Biol Chem. 2003;278:46741–46749. doi: 10.1074/jbc.M306451200. [DOI] [PubMed] [Google Scholar]
  • 8.Canas PM, Porciúncula LO, Cunha GM, Silva CG, Machado NJ, Oliveira JM, Oliveira CR, Cunha RA. Adenosine A2A receptor blockade prevents synaptotoxicity and memory dysfunction caused by beta-amyloid peptides via p38 mitogen-activated protein kinase pathway. J Neurosci. 2009;29:14741–14751. doi: 10.1523/JNEUROSCI.3728-09.2009. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 9.Canas PM, Porciúncula LO, Simões AP, Augusto E, Silva HB, Machado NJ, Gonçalves N, Alfaro TM, Gonçalves FQ, Araújo IM, Real JI, Coelho JE, Andrade GM, Almeida RD, Chen JF, Köfalvi A, Agostinho P, Cunha RA. Neuronal adenosine A2A receptors are critical mediators of neurodegeneration triggered by convulsions. eNeuro. 2018;5:ENEURO.0385-18.2018. doi: 10.1523/ENEURO.0385-18.2018. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 10.Charvin D, Medori R, Hauser RA, Rascol O. Therapeutic strategies for Parkinson disease: beyond dopaminergic drugs. Nat Rev Drug Discov. 2018;17:804–822. doi: 10.1038/nrd.2018.136. [DOI] [PubMed] [Google Scholar]
  • 11.Chaudhuri KR, Healy DG, Schapira AH, National Institute for Clinical Excellence Non-motor symptoms of Parkinson’s disease: diagnosis and management. Lancet Neurol. 2006;5:235–245. doi: 10.1016/S1474-4422(06)70373-8. [DOI] [PubMed] [Google Scholar]
  • 12.Chen JF, Huang Z, Ma J, Zhu J, Moratalla R, Standaert D, Moskowitz MA, Fink JS, Schwarzschild MA. A2A adenosine receptor deficiency attenuates brain injury induced by transient focal ischemia in mice. J Neurosci. 1999;19:9192–9200. doi: 10.1523/JNEUROSCI.19-21-09192.1999. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 13.Chen JF, Xu K, Petzer JP, Staal R, Xu YH, Beilstein M, Sonsalla PK, Castagnoli K, Castagnoli N, Jr, Schwarzschild MA. Neuroprotection by caffeine and A2A adenosine receptor inactivation in a model of Parkinson's disease. J Neurosci. 2001;21:RC143. doi: 10.1523/JNEUROSCI.21-10-j0001.2001. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 14.Chen JF, Eltzschig HK, Fredholm BB. Adenosine receptors as drug targets – what are the challenges? Nature Rev Drug Disc. 2013;12:265–286. doi: 10.1038/nrd3955. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 15.Cho BH, Choi SM, Kim JT, Kim BC. Association of coffee consumption and non-motor symptoms in drug-naïve, early-stage Parkinson's disease. Parkinsonism Relat Disord. 2018;50:42–47. doi: 10.1016/j.parkreldis.2018.02.016. [DOI] [PubMed] [Google Scholar]
  • 16.Coelho JE, Alves P, Canas PM, Valadas JS, Shmidt T, Batalha VL, Ferreira DG, Ribeiro JA, Bader M, Cunha RA, do Couto FS, Lopes LV. Overexpression of adenosine A2A receptors in rats: effects on depression, locomotion, and anxiety. Front Psychiatry. 2014;5:67. doi: 10.3389/fpsyt.2014.00067. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 17.Cunha RA. How does adenosine control neuronal dysfunction and neurodegeneration? J Neurochem. 2016;139:1019–1055. doi: 10.1111/jnc.13724. [DOI] [PubMed] [Google Scholar]
  • 18.Cunha RA, Ferré S, Vaugeois JM, Chen JF. Potential therapeutic interest of adenosine A2A receptors in psychiatric disorders. Curr Pharm Des. 2008;14:1512–1524. doi: 10.2174/138161208784480090. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 19.Cutler DL, Tendolkar A, Grachev ID. Safety, tolerability and pharmacokinetics after single and multiple doses of preladenant (SCH420814) administered in healthy subjects. J Clin Pharm Ther. 2012;37:578–587. doi: 10.1111/j.1365-2710.2012.01349.x. [DOI] [PubMed] [Google Scholar]
  • 20.d'Alcantara P, Ledent C, Swillens S, Schiffmann SN. Inactivation of adenosine A2A receptor impairs long term potentiation in the accumbens nucleus without altering basal synaptic transmission. Neuroscience. 2001;107:455–464. doi: 10.1016/s0306-4522(01)00372-4. [DOI] [PubMed] [Google Scholar]
  • 21.Dall'Igna OP, Fett P, Gomes MW, Souza DO, Cunha RA, Lara DR. Caffeine and adenosine A2a receptor antagonists prevent beta-amyloid (25-35)-induced cognitive deficits in mice. Exp Neurol. 2007;203:241–245. doi: 10.1016/j.expneurol.2006.08.008. [DOI] [PubMed] [Google Scholar]
  • 22.Dungo R, Deeks ED. Istradefylline: first global approval. Drugs. 2013;73:875–882. doi: 10.1007/s40265-013-0066-7. [DOI] [PubMed] [Google Scholar]
  • 23.Factor SA, Wolski K, Togasaki DM, Huyck S, Cantillon M, Ho TW, Hauser RA, Pourcher E. Long-term safety and efficacy of preladenant in subjects with fluctuating Parkinson's disease. Mov Disord. 2013;28:817–820. doi: 10.1002/mds.25395. [DOI] [PubMed] [Google Scholar]
  • 24.Fernandez HH, Greeley DR, Zweig RM, Wojcieszek J, Mori A, Sussman NM, 6002-US-051 Study Group Istradefylline as monotherapy for Parkinson disease: results of the 6002-US-051 trial. Parkinsonism Relat Disord. 2010;16:16–20. doi: 10.1016/j.parkreldis.2009.06.008. [DOI] [PubMed] [Google Scholar]
  • 25.Ferré S, Fredholm BB, Morelli M, Popoli P, Fuxe K. Adenosine-dopamine receptor-receptor interactions as an integrative mechanism in the basal ganglia. Trends Neurosci. 1997;20:482–487. doi: 10.1016/s0166-2236(97)01096-5. [DOI] [PubMed] [Google Scholar]
  • 26.Flajolet M, Wang Z, Futter M, Shen W, Nuangchamnong N, Bendor J, Wallach I, Nairn AC, Surmeier DJ, Greengard P. FGF acts as a co-transmitter through adenosine A2A receptor to regulate synaptic plasticity. Nat Neurosci. 2008;11:1402–1409. doi: 10.1038/nn.2216. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 27.Fujioka S, Yoshida R, Nose K, Hayashi Y, Mishima T, Fukae J, Kitano K, Kikuchi H, Tsuboi Y. A new therapeutic strategy with istradefylline for postural deformities in Parkinson's disease. Neurol Neurochir Pol. 2019;53:291–295. doi: 10.5603/PJNNS.a2019.0036. [DOI] [PubMed] [Google Scholar]
  • 28.Gonçalves N, Simões AT, Cunha RA, de Almeida LP. Caffeine and adenosine A2A receptor inactivation decrease striatal neuropathology in a lentiviral-based model of Machado-Joseph disease. Ann Neurol. 2013;73:655–666. doi: 10.1002/ana.23866. [DOI] [PubMed] [Google Scholar]
  • 29.Hamza TH, Chen H, Hill-Burns EM, Rhodes SL, Montimurro J, Kay DM, Tenesa A, Kusel VI, Sheehan P, Eaaswarkhanth M, Yearout D, Samii A, Roberts JW, Agarwal P, Bordelon Y, Park Y, Wang L, Gao J, Vance JM, Kendler KS, Bacanu SA, Scott WK, Ritz B, Nutt J, Factor SA, Zabetian CP, Payami H. Genome-wide gene-environment study identifies glutamate receptor gene GRIN2A as a Parkinson's disease modifier gene via interaction with coffee. PLoS Genet. 2011;7:e1002237. doi: 10.1371/journal.pgen.1002237. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 30.Hauser RA, Shulman LM, Trugman JM, Roberts JW, Mori A, Ballerini R, Sussman NM, Istradefylline 6002-US-013 Study Group Study of istradefylline in patients with Parkinson's disease on levodopa with motor fluctuations. Mov Disord. 2008;23:2177–2185. doi: 10.1002/mds.22095. [DOI] [PubMed] [Google Scholar]
  • 31.Hauser RA, Cantillon M, Pourcher E, Micheli F, Mok V, Onofrj M, Huyck S, Wolski K. Preladenant in patients with Parkinson's disease and motor fluctuations: a phase 2, double-blind, randomised trial. Lancet Neurol. 2011;10:221–229. doi: 10.1016/S1474-4422(11)70012-6. [DOI] [PubMed] [Google Scholar]
  • 32.Hauser RA, Olanow CW, Kieburtz KD, Pourcher E, Docu-Axelerad A, Lew M, Kozyolkin O, Neale A, Resburg C, Meya U, Kenney C, Bandak S. Tozadenant (SYN115) in patients with Parkinson's disease who have motor fluctuations on levodopa: a phase 2b, double-blind, randomised trial. Lancet Neurol. 2014;13:767–776. doi: 10.1016/S1474-4422(14)70148-6. [DOI] [PubMed] [Google Scholar]
  • 33.Hauser RA, Stocchi F, Rascol O, Huyck SB, Capece R, Ho TW, Sklar P, Lines C, Michelson D, Hewitt D. Preladenant as an adjunctive therapy with levodopa in Parkinson disease: two randomized clinical trials and lessons learned. JAMA Neurol. 2015;72:1491–1500. doi: 10.1001/jamaneurol.2015.2268. [DOI] [PubMed] [Google Scholar]
  • 34.Hohoff C, Mullings EL, Heatherley SV, Freitag CM, Neumann LC, Domschke K, Krakowitzky P, Rothermundt M, Keck ME, Erhardt A, Unschuld PG, Jacob C, Fritze J, Bandelow B, Maier W, Holsboer F, Rogers PJ, Deckert J. Adenosine A2A receptor gene: evidence for association of risk variants with panic disorder and anxious personality. J Psychiatr Res. 2010;44:930–937. doi: 10.1016/j.jpsychires.2010.02.006. [DOI] [PubMed] [Google Scholar]
  • 35.Iijima M, Orimo S, Terashi H, Suzuki M, Hayashi A, Shimura H, Mitoma H, Kitagawa K, Okuma Y. Efficacy of istradefylline for gait disorders with freezing of gait in Parkinson's disease: a single-arm, open-label, prospective, multicenter study. Expert Opin Pharmacother. 2019;20:1405–1411. doi: 10.1080/14656566.2019.1614167. [DOI] [PubMed] [Google Scholar]
  • 36.Jenner P. An overview of adenosine A2A receptor antagonists in Parkinson's disease. Int Rev Neurobiol. 2014;119:71–86. doi: 10.1016/B978-0-12-801022-8.00003-9. [DOI] [PubMed] [Google Scholar]
  • 37.Jenner P, Mori A, Hauser R, Morelli M, Fredholm BB, Chen JF. Adenosine, adenosine A2A antagonists, and Parkinson's disease. Parkinsonism Relat Disord. 2009;15:406–413. doi: 10.1016/j.parkreldis.2008.12.006. [DOI] [PubMed] [Google Scholar]
  • 38.Kanda T, Jackson MJ, Smith LA, Pearce RK, Nakamura J, Kase H, Kuwana Y, Jenner P. Adenosine A2A antagonist: a novel antiparkinsonian agent that does not provoke dyskinesia in parkinsonian monkeys. Ann Neurol. 1998;43:507–513. doi: 10.1002/ana.410430415. [DOI] [PubMed] [Google Scholar]
  • 39.Kaster MP, Machado NJ, Silva HB, Nunes A, Ardais AP, Santana M, Baqi Y, Müller CE, Rodrigues AL, Porciúncula LO, Chen JF, Tomé ÂR, Agostinho P, Canas PM, Cunha RA. Caffeine acts through neuronal adenosine A2A receptors to prevent mood and memory dysfunction triggered by chronic stress. Proc Natl Acad Sci U S A. 2015;112:7833–7838. doi: 10.1073/pnas.1423088112. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 40.Kieburtz K, Olanow CW, Krishnaswami J, Resburg C, Kerwood F, Glass A, Kenney C. A phase 3 study of Tozadenant (TOZ-PD) as a maintenance therapy for patients with Parkinson’s disease experiencing motor fluctuations: characterization of study population. Neurology. 2018;90(15 Supplement):P2.045. [Google Scholar]
  • 41.Kim Y, Je Y, Giovannucci E. Coffee consumption and all-cause and cause-specific mortality: a meta-analysis by potential modifiers. Eur J Epidemiol. 2019;34:731–752. doi: 10.1007/s10654-019-00524-3. [DOI] [PubMed] [Google Scholar]
  • 42.Knutsen LJS, Weiss SM. KW-6002, Kyowa Hakko Kogyo. Curr Opin Investig Drugs. 2001;2:668–673. [PubMed] [Google Scholar]
  • 43.Ko WKD, Camus SM, Li Q, Yang J, McGuire S, Pioli EY, Bezard E. An evaluation of istradefylline treatment on Parkinsonian motor and cognitive deficits in 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-treated macaque models. Neuropharmacology. 2016;110:48–58. doi: 10.1016/j.neuropharm.2016.07.012. [DOI] [PubMed] [Google Scholar]
  • 44.Kondo T, Mizuno Y, Japanese Istradefylline Study Group A long-term study of istradefylline safety and efficacy in patients with Parkinson disease. Clin Neuropharmacol. 2015;38:41–46. doi: 10.1097/WNF.0000000000000073. [DOI] [PubMed] [Google Scholar]
  • 45.Landolt HP. “No thanks, coffee keeps me awake”: individual caffeine sensitivity depends on ADORA2A genotype. Sleep. 2012;35:899–900. doi: 10.5665/sleep.1942. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 46.LeWitt PA, Guttman M, Tetrud JW, Tuite PJ, Mori A, Chaikin P, Sussman NM, 6002-US-005 Study Group Adenosine A2A receptor antagonist istradefylline (KW-6002) reduces "off" time in Parkinson's disease: a double-blind, randomized, multicenter clinical trial (6002-US-005) Ann Neurol. 2008;63:295–302. doi: 10.1002/ana.21315. [DOI] [PubMed] [Google Scholar]
  • 47.Li W, Dai S, An J, Xiong R, Li P, Chen X, Zhao Y, Liu P, Wang H, Zhu P, Chen J, Zhou Y. Genetic inactivation of adenosine A2A receptors attenuates acute traumatic brain injury in the mouse cortical impact model. Exp Neurol. 2009;215:69–76. doi: 10.1016/j.expneurol.2008.09.012. [DOI] [PubMed] [Google Scholar]
  • 48.Li W, Silva HB, Real J, Wang YM, Rial D, Li P, Payen MP, Zhou Y, Muller CE, Tomé AR, Cunha RA, Chen JF. Inactivation of adenosine A2A receptors reverses working memory deficits at early stages of Huntington's disease models. Neurobiol Dis. 2015;79:70–80. doi: 10.1016/j.nbd.2015.03.030. [DOI] [PubMed] [Google Scholar]
  • 49.Li Y, He Y, Chen M, Pu Z, Chen L, Li P, Li B, Li H, Huang ZL, Li Z, Chen JF. Optogenetic activation of adenosine A2A receptor signaling in the dorsomedial striatopallidal neurons suppresses goal-directed behavior. Neuropsychopharmacology. 2016;41:1003–1013. doi: 10.1038/npp.2015.227. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 50.Lopes JP, Pliássova A, Cunha RA. The physiological effects of caffeine on synaptic transmission and plasticity in the mouse hippocampus selectively depend on adenosine A1 and A2A receptors. Biochem Pharmacol. 2019;166:313–321. doi: 10.1016/j.bcp.2019.06.008. [DOI] [PubMed] [Google Scholar]
  • 51.Matsuura K, Kajikawa H, Tabei KI, Satoh M, Kida H, Nakamura N, Tomimoto H. The effectiveness of istradefylline for the treatment of gait deficits and sleepiness in patients with Parkinson's disease. Neurosci Lett. 2018;662:158–161. doi: 10.1016/j.neulet.2017.10.018. [DOI] [PubMed] [Google Scholar]
  • 52.Mingote S, Font L, Farrar AM, Vontell R, Worden LT, Stopper CM, Port RG, Sink KS, Bunce JG, Chrobak JJ, Salamone JD (2008) Nucleus accumbens adenosine A2A receptors regulate exertion of effort by acting on the ventral striatopallidal pathway. J Neurosci 28:9037–9046 [DOI] [PMC free article] [PubMed]
  • 53.Mizuno Y, Hasegawa K, Kondo T, Kuno S, Yamamoto M, Japanese Istradefylline Study Group Clinical efficacy of istradefylline (KW-6002) in Parkinson's disease: a randomized, controlled study. Mov Disord. 2010;25:1437–1443. doi: 10.1002/mds.23107. [DOI] [PubMed] [Google Scholar]
  • 54.Mizuno Y, Kondo T, Japanese Istradefylline Study Group Adenosine A2A receptor antagonist istradefylline reduces daily OFF time in Parkinson's disease. Mov Disord. 2013;28:1138–1141. doi: 10.1002/mds.25418. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 55.Müller CE, Jacobson KA. Recent developments in adenosine receptor ligands and their potential as novel drugs. Biochim Biophys Acta. 2011;1808:1290–1308. doi: 10.1016/j.bbamem.2010.12.017. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 56.Nagayama H, Kano O, Murakami H, Ono K, Hamada M, Toda T, Sengoku R, Shimo Y, Hattori N. Effect of istradefylline on mood disorders in Parkinson's disease. J Neurol Sci. 2019;396:78–83. doi: 10.1016/j.jns.2018.11.005. [DOI] [PubMed] [Google Scholar]
  • 57.Ning YL, Yang N, Chen X, Xiong RP, Zhang XZ, Li P, Zhao Y, Chen XY, Liu P, Peng Y, Wang ZG, Chen JF, Zhou YG. Adenosine A2A receptor deficiency alleviates blast-induced cognitive dysfunction. J Cereb Blood Flow Metab. 2013;33:1789–1798. doi: 10.1038/jcbfm.2013.127. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 58.Oliveira S, Ardais AP, Bastos CR, Gazal M, Jansen K, de Mattos SL, da Silva RA, Kaster MP, Lara DR, Ghisleni G. Impact of genetic variations in ADORA2A gene on depression and symptoms: a cross-sectional population-based study. Purinergic Signal. 2019;15:37–44. doi: 10.1007/s11302-018-9635-2. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 59.O'Neill M, Brown VJ. The effect of striatal dopamine depletion and the adenosine A2A antagonist KW-6002 on reversal learning in rats. Neurobiol Learn Mem. 2007;88:75–81. doi: 10.1016/j.nlm.2007.03.003. [DOI] [PubMed] [Google Scholar]
  • 60.Pinna A. Adenosine A2A receptor antagonists in Parkinson's disease: progress in clinical trials from the newly approved istradefylline to drugs in early development and those already discontinued. CNS Drugs. 2014;28:455–474. doi: 10.1007/s40263-014-0161-7. [DOI] [PubMed] [Google Scholar]
  • 61.Popat RA, Van Den Eeden SK, Tanner CM, Kamel F, Umbach DM, Marder K, Mayeux R, Ritz B, Ross GW, Petrovitch H, Topol B, McGuire V, Costello S, Manthripragada AD, Southwick A, Myers RM, Nelson LM. Coffee, ADORA2A, and CYP1A2: the caffeine connection in Parkinson's disease. Eur J Neurol. 2011;18:756–765. doi: 10.1111/j.1468-1331.2011.03353.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 62.Powers KM, Kay DM, Factor SA, Zabetian CP, Higgins DS, Samii A, Nutt JG, Griffith A, Leis B, Roberts JW, Martinez ED, Montimurro JS, Checkoway H, Payami H. Combined effects of smoking, coffee, and NSAIDs on Parkinson's disease risk. Mov Disord. 2008;23:88–95. doi: 10.1002/mds.21782. [DOI] [PubMed] [Google Scholar]
  • 63.Richardson PJ, Kase H, Jenner PG. Adenosine A2A receptor antagonists as new agents for the treatment of Parkinson's disease. Trends Pharmacol Sci. 1997;18:338–344. doi: 10.1016/s0165-6147(97)01096-1. [DOI] [PubMed] [Google Scholar]
  • 64.Ross GW, Abbott RD, Petrovitch H, Morens DM, Grandinetti A, Tung KH, Tanner CM, Masaki KH, Blanchette PL, Curb JD, Popper JS, White LR. Association of coffee and caffeine intake with the risk of Parkinson disease. JAMA. 2000;283:2674–2679. doi: 10.1001/jama.283.20.2674. [DOI] [PubMed] [Google Scholar]
  • 65.Sääksjärvi K, Knekt P, Rissanen H, Laaksonen MA, Reunanen A, Männistö S. Prospective study of coffee consumption and risk of Parkinson's disease. Eur J Clin Nutr. 2008;62:908–915. doi: 10.1038/sj.ejcn.1602788. [DOI] [PubMed] [Google Scholar]
  • 66.Sako W, Murakami N, Motohama K, Izumi Y, Kaji R. The effect of istradefylline for Parkinson's disease: a meta-analysis. Sci Rep. 2017;7:18018. doi: 10.1038/s41598-017-18339-1. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 67.Schiffmann SN, Fisone G, Moresco R, Cunha RA, Ferré S. Adenosine A2A receptors and basal ganglia physiology. Prog Neurobiol. 2007;83:277–292. doi: 10.1016/j.pneurobio.2007.05.001. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 68.Schrag A. Psychiatric aspects of Parkinson’s disease: an update. J Neurol. 2004;251:795–804. doi: 10.1007/s00415-004-0483-3. [DOI] [PubMed] [Google Scholar]
  • 69.Schwarzschild MA, Agnati L, Fuxe K, Chen JF, Morelli M. Targeting adenosine A2A receptors in Parkinson's disease. Trends Neurosci. 2006;29:647–654. doi: 10.1016/j.tins.2006.09.004. [DOI] [PubMed] [Google Scholar]
  • 70.Shen HY, Chen JF. Adenosine A2A receptors in psychopharmacology: modulators of behavior, mood and cognition. Curr Neuropharmacol. 2009;7:195–206. doi: 10.2174/157015909789152191. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 71.Shryock JC, Belardinelli L. Adenosine and adenosine receptors in the cardiovascular system: biochemistry, physiology, and pharmacology. Am J Cardiol. 1997;79:2–10. doi: 10.1016/s0002-9149(97)00256-7. [DOI] [PubMed] [Google Scholar]
  • 72.Sitkovsky MV, Lukashev D, Apasov S, Kojima H, Koshiba M, Caldwell C, Ohta A, Thiel M. Physiological control of immune response and inflammatory tissue damage by hypoxia-inducible factors and adenosine A2A receptors. Annu Rev Immunol. 2004;22:657–682. doi: 10.1146/annurev.immunol.22.012703.104731. [DOI] [PubMed] [Google Scholar]
  • 73.Stacy M, Silver D, Mendis T, Sutton J, Mori A, Chaikin P, Sussman NM. A 12-week, placebo-controlled study (6002-US-006) of istradefylline in Parkinson disease. Neurology. 2008;70:2233–2240. doi: 10.1212/01.wnl.0000313834.22171.17. [DOI] [PubMed] [Google Scholar]
  • 74.Stocchi F, Rascol O, Hauser RA, Huyck S, Tzontcheva A, Capece R, Ho TW, Sklar P, Lines C, Michelson D, Hewitt DJ, Preladenant Early Parkinson Disease Study Group Randomized trial of preladenant, given as monotherapy, in patients with early Parkinson disease. Neurology. 2007;88:2198–2206. doi: 10.1212/WNL.0000000000004003. [DOI] [PubMed] [Google Scholar]
  • 75.Surmeier DJ, Ding J, Day M, Wang Z, Shen W. D1 and D2 dopamine-receptor modulation of striatal glutamatergic signaling in striatal medium spiny neurons. Trends Neurosci. 2007;30:228–235. doi: 10.1016/j.tins.2007.03.008. [DOI] [PubMed] [Google Scholar]
  • 76.Takahashi M, Fujita M, Asai N, Saki M, Mori A. Safety and effectiveness of istradefylline in patients with Parkinson's disease: interim analysis of a post-marketing surveillance study in Japan. Expert Opin Pharmacother. 2018;19:1635–1642. doi: 10.1080/14656566.2018.1518433. [DOI] [PubMed] [Google Scholar]
  • 77.Tejani FH, Thompson RC, Iskandrian AE, McNutt BE, Franks B. Effect of caffeine on SPECT myocardial perfusion imaging during regadenoson pharmacologic stress: rationale and design of a prospective, randomized, multicenter study. J Nucl Cardiol. 2011;18:73–81. doi: 10.1007/s12350-010-9311-6. [DOI] [PubMed] [Google Scholar]
  • 78.Tolosa E, Compta Y, Gaig C. The premotor phase of Parkinson’s disease. Parkinsonism Relat Disord. 2007;13:S2–S7. doi: 10.1016/j.parkreldis.2007.06.007. [DOI] [PubMed] [Google Scholar]
  • 79.Torti M, Vacca L, Stocchi F. Istradefylline for the treatment of Parkinson's disease: is it a promising strategy? Exp Op Pharmacother. 2018;19:1821–1828. doi: 10.1080/14656566.2018.1524876. [DOI] [PubMed] [Google Scholar]
  • 80.Wei CJ, Augusto E, Gomes CA, Singer P, Wang Y, Boison D, Cunha RA, Yee BK, Chen JF. Regulation of fear responses by striatal and extrastriatal adenosine A2A receptors in forebrain. Biol Psychiatry. 2014;75:855–863. doi: 10.1016/j.biopsych.2013.05.003. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 81.Xiao D, Cassin JJ, Healy B, Burdett TC, Chen JF, Fredholm BB, Schwarzschild MA. Deletion of adenosine A1 or A2A receptors reduces L-3,4-dihydroxyphenylalanine-induced dyskinesia in a model of Parkinson's disease. Brain Res. 2011;1367:310–318. doi: 10.1016/j.brainres.2010.08.099. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 82.Yang A, Palmer AA, de Wit H. Genetics of caffeine consumption and responses to caffeine. Psychopharmacology. 2010;211:245–257. doi: 10.1007/s00213-010-1900-1. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 83.Zheng J, Zhang X, Zhen X. Development of adenosine A2A receptor antagonists for the treatment of Parkinson's disease: a recent update and challenge. ACS Chem Neurosci. 2019;10:783–791. doi: 10.1021/acschemneuro.8b00313. [DOI] [PubMed] [Google Scholar]
  • 84.Zhou SJ, Zhu ME, Shu D, Du XP, Song XH, Wang XT, Zheng RY, Cai XH, Chen JF, He JC. Preferential enhancement of working memory in mice lacking adenosine A2A receptors. Brain Res. 2009;1303:74–83. doi: 10.1016/j.brainres.2009.09.082. [DOI] [PubMed] [Google Scholar]

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