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Current Traditional Medicine


ISSN (Print): 2215-0838
ISSN (Online): 2215-0846

Review Article

Role of Caffeine in Inducing Anxiety by Reducing Brain Serotonin Synthesis Blocking Adenosine Receptors (A1, A2A, A2B, and A3)

Author(s): Pooja Verma, Rohit Dutt and Siraj Anwar*

Volume 8, Issue 4, 2022

Published on: 20 May, 2022

Article ID: e210322202482 Pages: 9

DOI: 10.2174/2215083808666220321145436

Price: $65


Caffeine is well-known for its stimulant characteristics and is included in a wide variety of foods, drinks, and pharmaceutical formulations worldwide. However, the methods by which caffeine exerts its effects on the brain were unknown until the past decade, when the development of strong research tools enabled scientists to explore the drug's neuropharmacological and biochemical characteristics. Serotonin, especially in sensitive people, also tends to decrease anxiety. Most of their biological effects are caused by antagonising all kinds of adenosine receptors (ARs): A1, A2A, A2B, and A3. Serotonin is a key Central Nervous System (CNS) neurotransmitter. The deregulation of the transmission of serotonin in the CNS is known to be associated with many human mental illnesses, including impulsive aggressiveness, depression, and anxiety disorders.

Keywords: Adenosine receptors, anxiety, caffeine, serotonin, psychotropic drugs, central nervous system (CNS).

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Rath M. Energy drinks: What is all the hype? The dangers of energy drink consumption. J Am Acad Nurse Pract 2012; 24(2): 70-6.
[] [PMID: 22324861]
Ahluwalia N, Herrick K. Caffeine intake from food and beverage sources and trends among children and adolescents in the United States: Review of national quantitative studies from 1999 to 2011. Adv Nutr 2015; 6(1): 102-11.
[] [PMID: 25593149]
Nardi AE, Lopes FL, Freire RC, et al. Panic disorder and social anxiety disorder subtypes in a caffeine challenge test. Psychiatry Res 2009; 169(2): 149-53.
[] [PMID: 19698996]
Wahlstrom D, White T, Luciana M. Neurobehavioral evidence for changes in dopamine system activity during adolescence. Neurosci Biobehav Rev 2010; 34(5): 631-48.
[] [PMID: 20026110]
Trapp GS, Allen K, O’Sullivan TA, Robinson M, Jacoby P, Oddy WH. Energy drink consumption is associated with anxiety in Australian young adult males. Depress Anxiety 2014; 31(5): 420-8.
[] [PMID: 24019267]
El Yacoubi M, Ledent C, Parmentier M, Costentin J, Vaugeois JM. The anxiogenic-like effect of caffeine in two experimental procedures measuring anxiety in the mouse is not shared by selective A(2A) adenosine receptor antagonists. Psychopharmacology (Berl) 2000; 148(2): 153-63.
[] [PMID: 10663430]
Ruxton CH. The suitability of caffeinated drinks for children: A systematic review of randomised controlled trials, observational studies and expert panel guidelines. J Hum Nutr Diet 2014; 27(4): 342-57.
[] [PMID: 25099503]
Qian L, Fan Y, Gao F, et al. Genetically determined levels of serum metabolites and risk of neuroticism: A Mendelian randomization study. Int J Neuropsychopharmacol 2021; 24(1): 32-9.
[] [PMID: 32808022]
Ardais AP, Borges MF, Rocha AS, Sallaberry C, Cunha RA, Porciúncula LO. Caffeine triggers behavioral and neurochemical alterations in adolescent rats. Neuroscience 2014; 270: 27-39.
[] [PMID: 24726984]
Donner NC, Johnson PL, Fitz SD, Kellen KE, Shekhar A, Lowry CA. Elevated tph2 mRNA expression in a rat model of chronic anxiety. Depress Anxiety 2012; 29(4): 307-19.
[] [PMID: 22511363]
Berger SM, Weber T, Perreau-Lenz S, et al. A functional Tph2 C1473G polymorphism causes an anxiety phenotype via compensatory changes in the serotonergic system. Neuropsychopharmacology 2012; 37(9): 1986-98.
[] [PMID: 22491354]
Ferré S. An update on the mechanisms of the psychostimulant effects of caffeine. J Neurochem 2008; 105(4): 1067-79.
[] [PMID: 18088379]
Solinas M, Ferré S, You ZB, Karcz-Kubicha M, Popoli P, Goldberg SR. Caffeine induces dopamine and glutamate release in the shell of the nucleus accumbens. J Neurosci 2002; 22(15): 6321-4.
[] [PMID: 12151508]
Bruce MS. The anxiogenic effects of caffeine. Postgrad Med J 1990; 66(Suppl. 2): S18-24.
[PMID: 2392393]
Boulenger JP, Patel J, Post RM, Parma AM, Marangos PJ. Chronic caffeine consumption increases the number of brain adenosine recep-tors. Life Sci 1983; 32(10): 1135-42.
[] [PMID: 6298543]
Daly JW. Caffeine analogs: Biomedical impact. Cell Mol Life Sci 2007; 64(16): 2153-69.
[] [PMID: 17514358]
Florio C, Prezioso A, Papaioannou A, Vertua R. Adenosine A1 receptors modulate anxiety in CD1 mice. Psychopharmacology (Berl) 1998; 136(4): 311-9.
[] [PMID: 9600575]
Walther DJ, Bader M. A unique central tryptophan hydroxylase isoform. Biochem Pharmacol 2003; 66(9): 1673-80.
[] [PMID: 14563478]
Mitsushima D, Yamada K, Takase K, Funabashi T, Kimura F. Sex differences in the basolateral amygdala: The extracellular levels of sero-tonin and dopamine, and their responses to restraint stress in rats. Eur J Neurosci 2006; 24(11): 3245-54.
[] [PMID: 17156385]
Ichiyama A, Nakamura S, Nishizuka Y, Hayaishi O. Enzymic studies on the biosynthesis of serotonin in mammalian brain. J Biol Chem 1970; 245(7): 1699-709.
[] [PMID: 5309585]
Hovatta I, Barlow C. Molecular genetics of anxiety in mice and men. Ann Med 2008; 40(2): 92-109.
[] [PMID: 18293140]
Kiesman WF, Zhao J, Conlon PR, et al. Potent and orally bioavailable 8-bicyclo[2.2.2]octylxanthines as adenosine A1 receptor antago-nists. J Med Chem 2006; 49(24): 7119-31.
[] [PMID: 17125264]
Daly JW, Hide I, Müller CE, Shamim M. Caffeine analogs: Structure-activity relationships at adenosine receptors. Pharmacology 1991; 42(6): 309-21.
[] [PMID: 1658821]
Vu CB, Kiesman WF, Conlon PR, et al. Tricyclic imidazoline derivatives as potent and selective adenosine A1 receptor antagonists. J Med Chem 2006; 49(24): 7132-9.
[] [PMID: 17125265]
Shimada J, Suzuki F, Nonaka H, Ishii A, Ichikawa S. (E)-1,3-dialkyl-7-methyl-8-(3,4,5-trimethoxystyryl)xanthines: Potent and selective adenosine A2 antagonists. J Med Chem 1992; 35(12): 2342-5.
[] [PMID: 1613758]
Yuzlenko O. Kieć-Kononowicz K. Potent adenosine A1 and A2A receptors antagonists: Recent developments. Curr Med Chem 2006; 13(30): 3609-25.
[] [PMID: 17168726]
Zablocki J, Kalla R, Perry T, et al. The discovery of a selective, high affinity A(2B) adenosine receptor antagonist for the potential treat-ment of asthma. Bioorg Med Chem Lett 2005; 15(3): 609-12.
[] [PMID: 15664822]
Fredholm BB, Arslan G, Halldner L, Kull B, Schulte G, Wasserman W. Structure and function of adenosine receptors and their genes. Naunyn Schmiedebergs archives of pharmacology 2000 Nov; 362(4): 364-74.
Baraldi PG, Tabrizi MA, Preti D, et al. Design, synthesis, and biological evaluation of new 8-heterocyclic xanthine derivatives as highly potent and selective human A2B adenosine receptor antagonists. J Med Chem 2004; 47(6): 1434-47.
[] [PMID: 14998332]
Robertson D, Wade D, Workman R, Woosley RL, Oates JA. Tolerance to the humoral and hemodynamic effects of caffeine in man. J Clin Invest 1981; 67(4): 1111-7.
[] [PMID: 7009653]
Gerwins P, Fredholm BB. Glucocorticoid receptor activation leads to up-regulation of adenosine A1 receptors and down-regulation of adenosine A2 responses in DDT1 MF-2 smooth muscle cells. Mol Pharmacol 1991; 40(2): 149-55.
[PMID: 1652051]
Dickenson JM, Hill SJ. Intracellular cross-talk between receptors coupled to phospholipase C via pertussis toxin-sensitive and insensitive G-proteins in DDT1MF-2 cells. Br J Pharmacol 1993; 109(3): 719-24.
[] [PMID: 8358567]
Schiffmann SN, Vanderhaeghen JJ. Caffeine regulates neurotensin and cholecystokinin messenger RNA expression in the rat striatum. Neuroscience 1993; 54(3): 681-9.
Hollingsworth EB, Sears EB, Daly JW. An activator of protein kinase C (phorbol-12-myristate-13-acetate) augments 2-chloroadenosine-elicited accumulation of cyclic AMP in guinea pig cerebral cortical particulate preparations. FEBS Lett 1985; 184(2): 339-42.
[] [PMID: 2987034]
Altiok N, Fredholm BB. Bradykinin inhibition of cyclic AMP accumulation in D384 astrocytoma cells. Evidence against a role of cyclic GMP. Neurochem Int 1992; 21(2): 209-13.
[] [PMID: 1284620]
Fredholm BB, Bättig K, Holmén J, Nehlig A, Zvartau EE. Actions of caffeine in the brain with special reference to factors that contribute to its widespread use. Pharmacol Rev 1999; 51(1): 83-133.
[PMID: 10049999]
Heckman MA, Weil J, Gonzalez de Mejia E. Caffeine (1, 3, 7-trimethylxanthine) in foods: A comprehensive review on consumption, functionality, safety, and regulatory matters. J Food Sci 2010; 75(3): R77-87.
[] [PMID: 20492310]
Blanchard J, Sawers SJ. Comparative pharmacokinetics of caffeine in young and elderly men. J Pharmacokinet Biopharm 1983; 11(2): 109-26.
[] [PMID: 6886969]
Malinauskas BM, Aeby VG, Overton RF, Carpenter-Aeby T, Barber-Heidal K. A survey of energy drink consumption patterns among college students. Nutr J 2007; 6(1): 35.
[] [PMID: 17974021]
Kawachi I, Willett WC, Colditz GA, Stampfer MJ, Speizer FE. A prospective study of coffee drinking and suicide in women. Arch Intern Med 1996; 156(5): 521-5.
[] [PMID: 8604958]
Greden JF, Fontaine P, Lubetsky M, Chamberlin K. Anxiety and depression associated with caffeinism among psychiatric inpatients. Am J Psychiatry 1978; 135(8): 963-6.
[] [PMID: 665843]
Whalen DJ, Silk JS, Semel M, et al. Caffeine consumption, sleep, and affect in the natural environments of depressed youth and healthy controls. J Pediatr Psychol 2008; 33(4): 358-67.
[] [PMID: 17947257]
Smith EE, Kosslyn SM. Cognitive psychology: Mind and brain. San Francisco: Academia 2020.
Mahoney CR, Brunyé TT, Giles GE. 14 caffeine effects on aggression and risky decision making. In: Lieberman HR, Kanarek RB, Eds. Diet, Brain, Behavior: Practical Implications. Boca Raton: CRC Press 2011.
Jarvis MJ. Does caffeine intake enhance absolute levels of cognitive performance? Psychopharmacology (Berl) 1993; 110(1-2): 45-52.
[] [PMID: 7870897]
Hameleers PA, Van Boxtel MP, Hogervorst E, et al. Habitual caffeine consumption and its relation to memory, attention, planning capacity and psychomotor performance across multiple age groups. Hum Psychopharmacol 2000; 15(8): 573-81.
[] [PMID: 12404609]
Johnson-Kozlow M, Kritz-Silverstein D, Barrett-Connor E, Morton D. Coffee consumption and cognitive function among older adults. Am J Epidemiol 2002; 156(9): 842-50.
[] [PMID: 12397002]
Soroko S, Chang J, Barrett-Connor E. Reasons for changing caffeinated coffee consumption: The Rancho Bernardo Study. J Am Coll Nutr 1996; 15(1): 97-101.
[] [PMID: 8632123]
Cappelletti S, Piacentino D, Sani G, Aromatario M. Caffeine: Cognitive and physical performance enhancer or psychoactive drug? Curr Neuropharmacol 2015; 13(1): 71-88.
[] [PMID: 26074744]
Harvanko AM, Derbyshire KL, Schreiber LR, Grant JE. The effect of self-regulated caffeine use on cognition in young adults. Hum Psychopharmacol 2015; 30(2): 123-30.
[] [PMID: 25689284]
Kamimori GH, Karyekar CS, Otterstetter R, et al. The rate of absorption and relative bioavailability of caffeine administered in chewing gum versus capsules to normal healthy volunteers. Int J Pharm 2002; 234(1-2): 159-67.
[] [PMID: 11839447]
Peterson S, Schwarz Y, Li SS, et al. CYP1A2, GSTM1, and GSTT1 polymorphisms and diet effects on CYP1A2 activity in a crossover feeding trial. Cancer Epidemiol Biomarkers Prev 2009; 18(11): 3118-25.
[] [PMID: 19843669]
Fredholm BB, Abbracchio MP, Burnstock G, et al. Nomenclature and classification of purinoceptors. Pharmacol Rev 1994; 46(2): 143-56.
[PMID: 7938164]
Fredholm BB. Are methylxanthine effects due to antagonism of endogenous adenosine? Trends Pharmacol Sci 1979; 1(1): 129-32.
Landolt HP. Sleep homeostasis: A role for adenosine in humans? Biochem Pharmacol 2008; 75(11): 2070-9.
[] [PMID: 18384754]
Okada M, Kawata Y, Murakami T, et al. Differential effects of adenosine receptor subtypes on release and reuptake of hippocampal sero-tonin. Eur J Neurosci 1999; 11(1): 1-9.
[] [PMID: 9987006]
Ullrich S, de Vries YC, Kühn S, Repantis D, Dresler M, Ohla K. Feeling smart: Effects of caffeine and glucose on cognition, mood and self-judgment. Physiol Behav 2015; 151: 629-37.
[] [PMID: 26320858]
Davis JK, Green JM. Caffeine and anaerobic performance: Ergogenic value and mechanisms of action. Sports Med 2009; 39(10): 813-32.
[] [PMID: 19757860]
Ferré S. Role of the central ascending neurotransmitter systems in the psychostimulant effects of caffeine. J Alzheimers Dis 2010; 20(s1)(Suppl. 1): S35-49.
[] [PMID: 20182056]
Doherty M, Smith PM. Effects of caffeine ingestion on exercise testing: A meta-analysis. Int J Sport Nutr Exerc Metab 2004; 14(6): 626-46.
[] [PMID: 15657469]

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