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Caffeine and the olfactory bulb

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Abstract

Caffeine, a popular CNS stimulant, is the most widely used neuroactive drug. Present in coffee, tea, chocolate, and soft drinks as well as over-the-counter and prescription medications, it influences millions of users. This agent has achieved recent notoriety because its dependency consequences and addictive potential have been re-examined and emphasized. Caffeine's central actions are thought to be mediated through adenosine (A) receptors and monoamine neurotransmitters. The present article suggests that the olfactory bulb (OB) may be an important site in the brain that is responsible for caffeine's central actions in several species. This conclusion is based on the extraordinarily robust and selective effects of caffeine on norepinephrine (NE), dopamine (DA), and particularly serotonin (5HT) utilization in the OB of mice. We believe that these phonomena should be given appropriate consideration as a basis for caffeine's central actions, even in primates. Concurrently, we review a rich rodent literature concerned with A, 5HT, NE, and DA receptors in the OB and related structures along with other monoamine parameters. We also review a more limited literature concerned with the primate OB. Finally, we cite the literature that treats the dependency and addictive effects of caffeine in humans, and relate the findings to possible olfactory mechanisms.

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References

  • Appel N. M., Mitchell W. M., Contrera, J. F., and De Souza E. B. (1990) Effects of high dose fenfluramine treatment on monoamine uptake sites in rat brain: assessment using quantitative autoradiography.Synapse 6, 33–44.

    Article  CAS  PubMed  Google Scholar 

  • Bassett J. L., Shipley M. T., and Foote S. L. (1992) Localization of corticotropin-releasing factor-like immunoreactivity in monkey olfactory bulb and secondary olfactory areas.J. Comp. Neurol. 316(3), 348–362.

    Article  CAS  PubMed  Google Scholar 

  • Benowitz N. L. (1990) Clinical pharmacology of caffeine.Ann. Rev. Med. 41, 277–288.

    Article  CAS  PubMed  Google Scholar 

  • Braddock S. R., Grafe M. R., and Jones K. L. (1995) Development of the olfactory nerve: its relationship to the craniofacies.Teratology 51(4), 252–256.

    Article  CAS  PubMed  Google Scholar 

  • Calamandrei G., Wilkinson L. S., and Keverne, E. B. (1992) Olfactory recognition of infants in laboratory mice: role of noradrenergic mechanisms.Physiol. Behav. 52(5), 901–907.

    Article  CAS  PubMed  Google Scholar 

  • Chou T. (1992), Wake up and smell the coffee. Caffeine, coffee and the medical consequences.West. J. Med. 157(5), 544–553.

    CAS  PubMed  Google Scholar 

  • Clans H. L., Moses H. II, and Beaulieu, D. M. (1974) The influence of caffeine on d-amphetamine and apomorphine-induced stereotyped behavior.Life Sci. 14, 1493–1500.

    Article  Google Scholar 

  • Daly J. W. (1993) Mechanism of action of caffeine, inCoffeine Coffee, and Health (Garattini S., ed.) Raven, New York, pp. 97–150.

    Google Scholar 

  • Elkind A. H. (1991) Drug abuse and headache.Med. Clin. North Am. 75(3), 717–732.

    CAS  PubMed  Google Scholar 

  • Erfurth A., and Schmauss M. (1990) [Adenosine and methylxanthines in the central nervous system — on their significance for psychiatry and neurology] Adenosine und Methylxanthine im Zentralnervensystem — zur Bedeutung für Psychiatrie und Neurologie.Fortschr. Neurol. Psychiatr. 58(4), 137–147.

    CAS  PubMed  Google Scholar 

  • Erinoff L. and Snodgrass S. R. (1986) Effects of adult or neonatal treatment with 6-hydroxydopamine or 5,7-dihydroxytryptamine on locomotor activity, monoamine levels, and response to caffeine.Pharmacol. Biochem. Behav. 24, 1039–1045.

    Article  CAS  PubMed  Google Scholar 

  • Evans S. M. and Griffith R. R. (1992) Caffeine tolerance and choice in humans.Psychopharmacology 108(1–2), 59–69.

    Google Scholar 

  • Fastbom, J., Pazos, A., Probst, A. and Placios, J. M. (1987) The distribution of adenosine A1 receptors and 5′-nucleotidase in the human brain: a quantitative autoradiographic study.Neuroscience 22(3), 8130–8126.

    Google Scholar 

  • Ferré S., von Euler G., Johansson B., Fredholm B. B. and Fuxe K. (1991) Stimulation of high-affinity adenosine A2 receptors decreases the affinity of dopamine D2 receptors in rat striatal membranes.Proc. Natl. Acad. Sci. USA 88, 7238–7241.

    Article  PubMed  Google Scholar 

  • Fishette C. T., Nock B., and Renner K. (1987) Effects of 5,7-dihydroxy-tryptamine on serotonin 1 and serotonin 2 receptors throughout the rat central nervous system using quantitative autoradiography.Brain Res. 421, 263–279.

    Article  Google Scholar 

  • Fredholm, B. B. (1995) Adenosine, adenosine receptors and the actions of caffeine.Pharmacol. Toxicol. 45, 43–85.

    Google Scholar 

  • Graham K. (1988) Reasons for consumption and heavy caffeine use: generalization of a model based on alcohol research.Addict. Behav. 13(2), 209–214.

    Article  CAS  PubMed  Google Scholar 

  • Griffiths R. R., Bigelow G. E. and Liebson I. A. (1986) Human coffee drinking: reinforcing and physical dependence producing effects of caffeine.J. Pharmacol. Exp. Ther. 239, 416–425.

    CAS  PubMed  Google Scholar 

  • Hadfield M. G. (1995) Cocaine: selective regional effects on central monoamines.Mol. Neurobiol. 11, 47–54.

    CAS  PubMed  Google Scholar 

  • Hadfield M. G., and Milio C. (1987a) HPLC determination of monoamines in rat brain after enzymatic treatment with ascorbate oxidase and sulfatase.J. Liquid Chromatgr. 10, 2047–2052.

    Article  Google Scholar 

  • Hadfield M. G. and Milio C. (1987b) Rimcazole (BW 234 U) and regional monoamine concentrations in mouse brain.Life Sci. 40, 2087–2090.

    Article  CAS  PubMed  Google Scholar 

  • Hadfield M. G. and Milio C. (1987c) Simultaneous HPLC analysis of catecholamines and indoleamines in mouse brain tissue following acetate extractions and treatment with ascorbate oxidase.J. Liquid Chromatgr. 10, 2039–2046.

    Google Scholar 

  • Hadfield, M. G. and Milio C. (1989) Caffeine and regional brain monoamine utilization in mice.Life Sci. 45, 2637–2644.

    Article  CAS  PubMed  Google Scholar 

  • Hadfield M. G. and Milio C. (1992) Cocaine and regional brain monoamines in mice.Pharmacol. Biochem. Behav. 43, 395–403.

    Article  CAS  PubMed  Google Scholar 

  • Hadfield M. G., Crane P., King M. E., Nugent E. A., Milio C., Powell M. D., and Narasimhachari N. (1986a) Determination of 13 catecholamines, indole-amines, metabolites and precursors in less than 20 minutes during a single HPLC run.J. Liquid Chromatogr. 8, 2689–2697.

    Article  Google Scholar 

  • Hadfield M. G., Milio C., and Narasimhachari N. (1986b) HPLC determination of several monoamines in brain tissues of DBA/2 mice during a single run of 20–25 minutes without prior cleanup of samples.J. Chromatogr. 369, 449–453.

    Article  CAS  PubMed  Google Scholar 

  • Hoffman B. J. and Mezey E. (1989), Distribution of serotonin 5-HT 1c receptor mRNA in adult rat brain.FEBS Lett. 247, 453–462.

    Article  CAS  PubMed  Google Scholar 

  • Jack J. E. (1991)Caffeine and Health [Psychopathology]. Academic, New York.

    Google Scholar 

  • Jarvis M. F. and Williams M. (1990) Direct autoradiographic localization of adenosine A2 receptors in the rat brain using the A2-selective agonist, [3H]CGS 21680.Eur. J. Pharmacol. 68(2), 243–246.

    Google Scholar 

  • Jarvis M. F., Jackson R. H., and Williams M. (1989) Autoradiographic characterization of high-affinity adenosine A2 receptors in rat brain.Brain Res. 484, 111–118.

    Article  CAS  PubMed  Google Scholar 

  • Kirch D. G., Taylor T. R., Gerhardt G. A., Benowitz N., Stephen C., Freedman R., and Wyatt R. J. (1990) Effect of chronic caffeine administration on monoamine and monoamine metabolite concentrations in rat brain.Neuropharmacology 29(6), 599–602.

    Article  CAS  PubMed  Google Scholar 

  • Kitatani T., Watanabe Y., and Shibuy T. (1993) Different effects of methylxanthines on central serotonergic postsynaptic neurons in a mouse behavioral model.Pharmacol. Biochem. Behav. 44, 457–461.

    Article  CAS  PubMed  Google Scholar 

  • Koenigsberg H. W., Pollak C. P., and Fine, J. (1993) Olfactory hallucinations after the infusion of caffeine during sleep.Am. J. Psychiatr. 150(12), 1897,1898.

    CAS  PubMed  Google Scholar 

  • Kozlowski L. T., Henningfield J. E., Keenan R. M., Lei H., Leigh G., Jelineck L. C., Pope M. A., and Haertzen C. A. (1993) Patterns of alcohol, cigarette and caffeine and other drug use in two drug abusing populations.J. Subst. Abuse Treat. 10(2), 171–193.

    Article  CAS  PubMed  Google Scholar 

  • Kratskin I. L. (1995) Functional anatomy, central connections, and neurochemistry of the mammalina olfactory bulb, in (Doty R. L., ed.),Handbook of Olfaction and Gustation Marcell Dekker, New York, pp. 103–126.

    Google Scholar 

  • Lee K. S., and Reddington M. (1986) Autoradiographic evidence for multiple CNS binding sites for adenosine derivatives.Neuroscience 19(2), 535–549.

    Article  CAS  PubMed  Google Scholar 

  • Lumia A. R., Teicher M. H., Salchli F., Ayers E., and Possidente B. (1992) Olfactory bulbectomy as a model for agitated hyposerotonergic depression.Brain Res. 587(2), 181–185.

    Article  CAS  PubMed  Google Scholar 

  • Mamounas L. A., Mullen C. A., O'Hearn E., and Molliver M. E. (1991) Dual serotoninergic projections to forebrain in the rat: morphologically distinct 5 HT axon terminals exhibit differential vulnerability to neurotoxic amphetamine derivatives.J. Comp. Neurol. 314(3), 558–568.

    Article  CAS  PubMed  Google Scholar 

  • Martin G. R. and Humphrey, P. P. A. (1994) Receptors for 5-hydroxy-tryptamine: Current perspectives on classification and nomenclature.Neuropharmacology 533, 261–273.

    Article  Google Scholar 

  • McKenna D. J., Maxarali A. J., Hoffman A. J., Nichols D. E., Mathis C. A., and Saavedra, J. M. (1989) Common receptors for hallucinogens in rat brain: a comparative autoradiographic study using [1251]LSD and [1251] DOI, a new psychomimetic radioligand.Brain Res. 476, 45–56.

    Article  CAS  PubMed  Google Scholar 

  • McKenna D. J. and Saavedra J. M. (1987) Autoradiography of LSD and 2,5′ dimethoxyphenylisopropylamine psychomimetics demonstrates regional, specific cross-displacement in the rat brain.Eur. J. Pharmacol. 142, 313–315.

    Article  CAS  PubMed  Google Scholar 

  • McLean J. H., Darby-King A., Sullivan R. M., and King S. R. (1993). Serotonergic influence on olfactory learning in the neonate rate.Behav. Neural. Biol. 60(2), 152–162.

    Article  CAS  PubMed  Google Scholar 

  • Mestre N., Petter A., and Bons N. (1992) Systematisation of the olfactory bulb efferent projections in a lemurian, primate:Microcebus murinus.J. Hirnforsch. 33(2), 173–184.

    CAS  PubMed  Google Scholar 

  • Mick G., Cooper H., and Magnin M. (1993) Retinal projection to the olfactory tubercle and basal telencephalon in primates.J. Comp. Neurol. 327(2), 205–219.

    Article  CAS  PubMed  Google Scholar 

  • Milio C. and Hadfield M. G. (1992) Ethanol alters monoamines in specific brain regions.Brain Res. Bull. 29, 599–603.

    Article  CAS  PubMed  Google Scholar 

  • Minana M. D. and Grisolia S. (1986) Caffeine ingestion by rats increases noradrenaline turnover and results in self-biting.J. Neurochem. 47(3)., 728–732.

    Article  CAS  PubMed  Google Scholar 

  • Misra A. L., Vadlamani, N. L., and Pontan R. B. (1986) Effect of caffeine on cocaine locomotor of caffeine on cocaine locomotor stimulant activity in rats.Pharmacol. Biochem. Behav. 24, 761–764.

    Article  CAS  PubMed  Google Scholar 

  • Missak S. S. (1991) Exploring the role of an endogenous caffiene-like substance in the pathogenesis of schizophrenia.Med. Hypotheses 36(2), 157–161.

    Article  CAS  PubMed  Google Scholar 

  • Muller F., and O'Rahilly R. (1989) The human brain at stage 17, including the appearance of the future olfactory bulb and the first amygdaloid nuclei.Anat. Embryol. 180(4), 353–369.

    Article  CAS  PubMed  Google Scholar 

  • Nehlig A., Daval J. L., and Debry G. (1992), Caffeine and the central nervous system: mechanisms of action, biochemical, metabolic and psychostimulation effects.Brain Res. Rev. 17(2), 139–170.

    Article  CAS  PubMed  Google Scholar 

  • Pazos A., Cardias R., and Palaces J. M. (1985a) Quantitative autoradiogrpahic mapping of serotonin receptors in the rat brain. I. Serotonin-1 receptors.Brain Res. 346, 205–230.

    Article  CAS  PubMed  Google Scholar 

  • Pazos A., Cardias R., and Palaces, J. M. (1985b) Quantitative autoradiographic mapping of serotonin receptors in the rat brain. II. serotonin-2 receptors.Brain Res. 346, 231–249.

    Article  CAS  PubMed  Google Scholar 

  • Perret M., and Schilling A. (1993) Response to short photoperiod and spontaneous sexual recrudescence in the lesser mouse lemur: role of olfactory bulb removal.J. Endocrinol. 137(3), 511–518.

    Article  CAS  PubMed  Google Scholar 

  • Petersen E. P., Abhold R. H., Camara C. G., Wright J. W. and Harding J. W. (1985) Characterization of angiotensin binding in the African green monkey.Brain Res. 341(1), 139–146.

    Article  CAS  PubMed  Google Scholar 

  • Reith M. E. (1990) 5-HT3 receptor antagonists attenuate cocaine-induced locomotion in mice.Eur. J. Pharmacol. 186(2–3), 327–330.

    Article  CAS  PubMed  Google Scholar 

  • Reyher C. K. (1988) Persistence of the pars externa system of the anterior olfactory nucleus in a microsmatic primate, Callithrix jacchus.Brain Res. 475(1), 169–175.

    Article  Google Scholar 

  • Sanides-Kohlrausch C., and Wahle P. (1991) Distribution and morphology of substance P-immunoreactive structures in the olfactory bulb and olfactory peduncle of the common marmoset (Callithrix jacchus), a primate species.Neurosci. Lett. 131(1), 117–120.

    Article  CAS  PubMed  Google Scholar 

  • Sawynok J. and Yaksh T. L. (1993) Caffeine as an analgesic adjuvant: a review of pharmacology and mechanisms of action.Pharmacol. Rev. 45, 43–85.

    CAS  PubMed  Google Scholar 

  • Schechter M. D. (1977) Caffeine potentiation of amphetamine: implications for hyperkinesis therapy.Pharmacol. Biochem. Behav. 6, 359–361.

    Article  CAS  PubMed  Google Scholar 

  • Senba E., Daddona P. E., and Nagy J. I. (1989) Adenosine deaminase-containing neurons in the olfactory system of the rat during development.Brain Res. Bull. 18(5), 635–648.

    Article  Google Scholar 

  • Shen Y., Monsma F. J. R., Metcalf M. A., Jose P. A., Hamblin M. W., and Sibley, D. R. (1993) Molecular cloning and expression of a 5-hydroxytryptamine 7 serotonin receptor subtype.J. Biol. Chem. 268(24), 18,200–18,204.

    CAS  Google Scholar 

  • Shi D., Nikodijevic O., Jacobson K. A., and Daly J. W. (1993) Chronic caffeine alters the density of adenosine, adrenergic, cholinergic, GABA, and serotonin receptors and calcium channels in mouse brain.Cell. Mol. Neurobiol. 13, 247–261.

    Article  CAS  PubMed  Google Scholar 

  • Stoner G. R., Skirboll L. R., Werkman S., and Hommer D. W. (1988) Preferential effects of caffeine on limbic and cortical dopamine systems.Biol. Psychiatr. 23, 761–768.

    Article  CAS  Google Scholar 

  • Strain E. C., Mumford G. H., Silverman K., and Griffiths, R. R. (1994) Caffeine dependence syndrome. Evidence from case histories and experimental evaluation.JAMA 272(13), 1043–1048.

    Article  CAS  PubMed  Google Scholar 

  • Waldek B. (1973) Sensitization by caffeine of central catecholamine receptors.J. Neural. Trans. 34, 61–72.

    Article  Google Scholar 

  • White B. C. and Keller G. E. II (1984) Caffeine pretreatment: enhancement and attenuation ofd-amphetamine-induced activity.Pharmacol. Biochem. Behav. 20, 383–386.

    Article  CAS  PubMed  Google Scholar 

  • White B. C., Simpson C. C., Adams J. E., and Harleins D., Jr. (1978) Monoamine synthesis and caffeine-induced locomotor activity.Neuropharmacology 17, 511–513.

    Article  CAS  PubMed  Google Scholar 

  • Wise R. A. (1987) The role of reward pathways in the development of drug dependence.Pharmacol. Ther 35(1–2), 227–263.

    Article  CAS  PubMed  Google Scholar 

  • Wortsman J. and Hughes L. F. (1996) Case report: olfactory function in a fertile eunuch with Kallmann syndrome.Am. J. Med. Sci. 311(3), 135–138.

    Article  CAS  PubMed  Google Scholar 

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  1. The Division of Neuropathology, Department of Pathology, Medical College of Virginia/Virginia Commonwealth University, 23298, Richmond, VA

    M. Gary Hadfield

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Hadfield, M.G. Caffeine and the olfactory bulb. Mol Neurobiol 15, 31–39 (1997). https://doi.org/10.1007/BF02740614

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