doi: 10.1159/000119183, Randall, P. A., Lee, C. A., Podurgiel, S. J., Hart, E., Yohn, S. E., Jones, M., et al. However, in rhesus monkeys intravenous (IV) caffeine (10.0 mg/kg) decreased percent of task completed, and breakpoint in a PR for palatable food (Buffalo et al., 1993), possibly because this dose directly administered in the blood stream resulted in higher levels in the brain. Psychol. Inflammation and its discontents: the role of cytokines in the pathophysiology of major depression. In conclusion, although further studies are needed, it appears that caffeine and selective adenosine receptor antagonists could be therapeutic agents for the treatment of motivational dysfunction in depression. Brain Res. Furthermore, a recent report indicates that istradefylline can improve fatigue-related symptoms in Parkinson’s disease patients (Abe et al., 2016; Sako et al., 2017).

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47, 199–201. The IV push is often followed with a flush of 10–20 mL of normal saline. doi: 10.1016/j.neuroscience.2005.01.014, Rees, K., Allen, D., and Lader, M. (1999). 23, 28–38. J. Pharmacol. Worth the “EEfRT”? (2012).

This behavioral effect was supported by changes in an intracellular marker of DA neurotransmission [phosphorylated form of DARPP-32; pDARPP-32(Thr34)] in the striatum (López-Cruz et al., 2018). The Diagnostic and Statistical Manual in its last edition (DMS-5) defines this disorder as a set of symptoms including: depressed mood, decreased interest or pleasure in almost all activities nearly every day, appetite changes (changes in body weight), sleep disturbances, feelings of worthlessness or guilt, diminished ability to concentrate or indecisiveness, psychomotor agitation or retardation and fatigue or loss of energy (American Psychiatric Association, 2013). J. Does psychomotor retardation define a clinically relevant phenotype of unipolar depression? 26, 1180–1188. Psychiatry 63, 7–8. Abstinence from intermediate doses in daily coffee and cola consumers (579 mg/day), increased ratings of drowsy/sleepy, fatigue/tired, lazy/sluggy/slow-moving, decreased ratings of active/energetic/excited and motivation to work, and impaired performance on psychomotor tasks (Liguori and Hughes, 1997). doi: 10.1016/j.jad.2010.08.004, Childs, E., and de Wit, H. (2008). (1997). What Is the Function of Adenosine Triphosphate. Behav. It also is responsible for the termination of epileptic seizure activity. This escape deficit induced by glutamate in the prefrontal cortex has been also associated with enhanced adenosine (Petty et al., 1985), since increases in glutamate are counterbalanced by an increase in adenosine production and release (Deckert and Gleiter, 1994; Kerkhofs et al., 2018). All these side effects could in fact worse the symptoms of MDD. Adenosine A2A receptor signaling provides inhibitory feedback on proinflammatory cytokine signaling in peripheral immune cells (Sitkovsky and Ohta, 2005). The many faces of fatigue in major depressive disorder. Clin. The four receptor subtypes are further classified based on their ability to either stimulate or inhibit adenylate cyclase activity.

A1R and A2AR, adenosine A1 and A2A receptors; D1, DA type 1 receptor; D2, DA type 2 receptor (adapted from Ferré, 2008).

Lorist, M. M., Snel, J., Kok, A., and Mulder, G. (1994). This causes an increase in coronary vasodilatation. Brain Res. doi: 10.1016/j.bbi.2014.05.018, Cocker, P. J., Hosking, J. G., Benoit, J., and Winstanley, C. A. doi: 10.1016/j.drugalcdep.2012.01.009, Kale, P. P., and Addepalli, V. (2014). Behav.

The adenosine A2A antagonist KF17837 reverses the locomotor suppression and tremulous jaw movements induced by haloperidol in rats: possible relevance to parkinsonism. Psychosomatics 37, 518–522. A within-subjects comparison of coffee and cola vehicles. Effort-related motivational effects of the pro-inflammatory cytokine interleukin 1-beta: studies with the concurrent fixed ratio 5/ chow feeding choice task. Exp. Protoc. Moreover, A2A KO mice were resistant to the effects of haloperidol on performance of the T-maze barrier task (Pardo et al., 2012). Purine nucleoside–mediated immobility in mice: reversal by antidepressants. Thus in the animal literature, as in the human data, there are studies showing how caffeine and selective adenosine antagonists affect the willingness to work depending on the demands of the task. A2A receptors are expressed at high levels in the striatum and olfactory bulbs and tubercle (Fredholm et al., 2011), but also in areas such as amygdala, hippocampus or prefrontal cortex (Cunha et al., 1994; Pandolfo et al., 2013; Simões et al., 2016). Toxicol. Nat. (2012). 26, 299–304. Brain Behav. Influence of caffeine on selective attention in well-rested and fatigued subjects. doi: 10.1007/BF02245659, SanMiguel, N., Pardo, M., Carratalá-Ros, C., López-Cruz, L., Salamone, J. D., and Correa, M. (2018). (2013). doi: 10.1176/ajp.135.8.963. J. Psychiatry Relat.

Behav. 7, 391–396. Psychopharmacol. Articles, Faculty of Medicine, University of Coimbra, Portugal. LXXXI. doi: 10.1007/s00213-004-2048-7, Pettibone, D. J., Totaro, J. JS has received grants from Merck-Serrono, Pfizer, Roche, Shire, and Prexa. Wikibuy Review: A Free Tool That Saves You Time and Money, 15 Creative Ways to Save Money That Actually Work. Trends Immunol. In these preclinical studies addressing the effort-related decision-making process, animals are given a choice between a more valued reinforcer that can only be obtained by engaging in a more demanding (higher effort) activity vs. a low effort/low value option. Psychopharmacology 104, 515–521.

[10], Extracellular adenosine concentrations from normal cells are approximately 300 nM; however, in response to cellular damage (e.g., in inflammatory or ischemic tissue), these concentrations are quickly elevated (600–1,200 nM). Psychol. The four receptor subtypes are further classified based on their ability to either stimulate or inhibit adenylate cyclase activity. (2008). Patients with high scores in psychomotor retardation also have longer duration of illness, an earlier age of onset, and more depressive episodes (Calugi et al., 2011; Gorwood et al., 2014). Hanff, T. C., Furst, S. J., and Minor, T. R. (2010). Psychol. A wide range of studies demonstrate that caffeine can increase alertness and subjective energy, and also reduce fatigue (Johnson et al., 1990b, 1991; Yu et al., 1991; Smith et al., 1992, 1997; Lieberman, 2001), thus acting as an ergogenic substance. (2010).

J. Soc.

Psychiatry 15, 377–386. Stress and adenosine: I.


[8] Individuals taking large quantities of methylxanthines may require increased doses of adenosine.
doi: 10.1016/S0197-0186(00)00034-6, Cunha, R. A. Moderate doses of caffeine and theophylline (5.0–20.0 mg/kg) increased responding on the low task with low response demands; a fixed interval 240 s (FI-240 s) schedule.

When adenosine binds to its receptors, neural activity slows down, and you feel sleepy. Neurotransmitters bind to receptors and consequently, specific ion channels open or close. In the present review, we focus on studies that assessed the effect of adenosine antagonists on different aspects of depression in humans, as well as in animal models. Psychopharmacology 85, 460–463. (2018).

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