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Vol. 51, Issue 1, 83-133, March 1999
Section of Molecular Neuropharmacology (B.B.F., J.H.), Department
of Physiology and Pharmacology, Karolinska Institutet, Stockholm,
Sweden; Behavioural Biology Laboratory (K.B.), Swiss Federal Institute
of Technology, Zürich, Switzerland; INSERM U 398 (A.N.),
Faculté de Médecine, Strasbourg Cedex, France; Department
of Psychopharmacology (E.E.Z.), Valdman Institute of Pharmacology,
Pavlov Medical University, St. Petersburg, Russia
I. Introduction
II. Consumption and Metabolism of Caffeine
A. Sources of Caffeine
B. Caffeine Absorption, Distribution, and Pharmacokinetics
C. Caffeine Metabolism
III. Molecular and Cellular Action of Caffeine in the Brain
A. Fundamental Biochemical Actions
B. Adenosine Levels in Brain and Other Tissues
C. Adenosine Acts on Several Types of G-Protein-Coupled Receptors
1. Receptor Subtypes.
2. Receptor Distribution.
D. Caffeine Affects Transmitter Release and Neuronal Firing Rates
via Actions on Adenosine A1 Receptors
E. Caffeine Effects on Dopaminergic Transmission Are Exerted Mainly
via Actions on Adenosine A2A Receptors
F. Identifying the Neuronal Substrates For Caffeine by Examining
Changes in Immediate Early Genes
High Dose Effects
G. Low Doses of Caffeine Selectively Decrease the Activity of
Striatopallidal Neurons in the Striatum and Their Counterparts in the
Nucleus Accumbens
IV. Actions of Caffeine on Brain Functions and Behavior
A. Activation of Dopaminergic Transmission and Effects on Motor
Behavior
B. Caffeine and Mood
C. Effects of Caffeine in the Cortex and HippocampusInformation
Processing and Performance
D. Effects on Sleep
E. Effects of Caffeine on Cerebral Blood Flow and Metabolism
F. Other Effects
V. Addiction and Drug Dependence
A. Definitions
B. On the Neuronal and Molecular Basis of Drug Reinforcement and
Addiction
VI. Caffeine Withdrawal and Relief of Abstinence Symptoms by
Caffeine
A. Animal Studies on Caffeine Withdrawal
B. Human Studies
C. Effect of Caffeine on Withdrawal Symptoms
VII. Tolerance to the Effects of Caffeine
A. Cardiovascular Effects
B. Effects on Sleep
C. Effects on Mood
D. Other Central Effects
E. Differences between Acute and Long-Term AdministrationEffect
Inversion
VIII. Caffeine Discrimination and Dose Adjustment in Animals and
Humans
A. Caffeine Discrimination in Animals
B. Caffeine Discrimination in humans
C. Dose Adjustment
IX. Reinforcing Effects of Caffeine
A. Reinforcement in Animals
1. Intravenous and Oral Self-Administration.
2. Reinforcing Effects of Caffeine: Place Conditioning.
B. Reinforcement in Humans
X. Possible Reinforcing Effects of Coffee, Independent of Caffeine
Content
XI. Comparisons with Known Addictive Compounds and Interactions
between Caffeine and Addictive Drugs
A. General Considerations
B. Interactions between Caffeine and Cocaine or Amphetamine
C. Interactions between Caffeine and Ethanol
D. Interactions between Caffeine and Nicotine
XII. Possible Harmful Effects of Caffeine at the Individual or
Social Level
Abuse or Misuse
XIII. Conclusions
Acknowledgments
References
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B. Johansson, L. Halldner, T. V. Dunwiddie, S. A. Masino, W. Poelchen, L. Gimenez-Llort, R. M. Escorihuela, A. Fernandez-Teruel, Z. Wiesenfeld-Hallin, X.-J. Xu, et al. Hyperalgesia, anxiety, and decreased hypoxic neuroprotection in mice lacking the adenosine A1 receptor PNAS, July 19, 2001; (2001) 161292398. [Abstract] [Full Text] [PDF]
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 P Terry, L Bergkvist, L Holmberg, and A Wolk Coffee consumption and risk of colorectal cancer in a population based prospective cohort of Swedish women Gut, July 1, 2001; 49(1): 87 - 90. [Abstract] [Full Text] [PDF]
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J. P. Wisor, S. Nishino, I. Sora, G. H. Uhl, E. Mignot, and D. M. Edgar Dopaminergic Role in Stimulant-Induced Wakefulness J. Neurosci., March 1, 2001; 21(5): 1787 - 1794. [Abstract] [Full Text] [PDF]
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J.-F. Chen, R. Moratalla, F. Impagnatiello, D. K. Grandy, B. Cuellar, M. Rubinstein, M. A. Beilstein, E. Hackett, J. S. Fink, M. J. Low, et al. The role of the D2 dopamine receptor (D2R) in A2A adenosine receptor (A2AR)-mediated behavioral and cellular responses as revealed by A2A and D2 receptor knockout mice PNAS, February 13, 2001; 98(4): 1970 - 1975. [Abstract] [Full Text] [PDF]
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E. Arrigoni, D. G. Rainnie, R. W. McCarley, and R. W. Greene Adenosine-Mediated Presynaptic Modulation of Glutamatergic Transmission in the Laterodorsal Tegmentum J. Neurosci., February 1, 2001; 21(3): 1076 - 1085. [Abstract] [Full Text] [PDF]
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M. Gasior, M. Jaszyna, J. Peters, and S. R. Goldberg Changes in the Ambulatory Activity and Discriminative Stimulus Effects of Psychostimulant Drugs in Rats Chronically Exposed to Caffeine: Effect of Caffeine Dose J. Pharmacol. Exp. Ther., December 1, 2000; 295(3): 1101 - 1111. [Abstract] [Full Text]
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B. Wilken, J. M. Ramirez, F. Hanefeld, and D. W. Richter Aminophylline modulation of the mouse respiratory network changes during postnatal maturation J Appl Physiol, November 1, 2000; 89(5): 2015 - 2022. [Abstract] [Full Text] [PDF]
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N. R. Zahniser, J. K. Simosky, R. D. Mayfield, C. A. Negri, T. Hanania, G. A. Larson, M. A. Kelly, D. K. Grandy, M. Rubinstein, M. J. Low, et al. Functional Uncoupling of Adenosine A2A Receptors and Reduced Response to Caffeine in Mice Lacking Dopamine D2 Receptors J. Neurosci., August 15, 2000; 20(16): 5949 - 5957. [Abstract] [Full Text] [PDF]
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 K. Varani, F. Portaluppi, S. Gessi, S. Merighi, E. Ongini, L. Belardinelli, and P. A. Borea Dose and Time Effects of Caffeine Intake on Human Platelet Adenosine A2A Receptors : Functional and Biochemical Aspects Circulation, July 18, 2000; 102(3): 285 - 289. [Abstract] [Full Text] [PDF]
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M. N. Alam, R. Szymusiak, H. Gong, J. King, and D. McGinty Adenosinergic modulation of rat basal forebrain neurons during sleep and waking: neuronal recording with microdialysis J. Physiol., December 15, 1999; 521(3): 679 - 690. [Abstract] [Full Text] [PDF]
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 B. Eskenazi Caffeine -- Filtering the Facts N. Engl. J. Med., November 25, 1999; 341(22): 1688 - 1689. [Full Text]
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K. M. Harris Calcium from internal stores modifies dendritic spine shape PNAS, October 26, 1999; 96(22): 12213 - 12215. [Full Text] [PDF]
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B. Johansson, L. Halldner, T. V. Dunwiddie, S. A. Masino, W. Poelchen, L. Gimenez-Llort, R. M. Escorihuela, A. Fernandez-Teruel, Z. Wiesenfeld-Hallin, X.-J. Xu, et al. Hyperalgesia, anxiety, and decreased hypoxic neuroprotection in mice lacking the adenosine A1 receptor PNAS, July 31, 2001; 98(16): 9407 - 9412. [Abstract] [Full Text] [PDF]
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J.-F. Chen, K. Xu, J. P. Petzer, R. Staal, Y.-H. Xu, M. Beilstein, P. K. Sonsalla, K. Castagnoli, N. Castagnoli Jr, and M. A. Schwarzschild Neuroprotection by Caffeine and A2A Adenosine Receptor Inactivation in a Model of Parkinson's Disease J. Neurosci., May 15, 2001; 21(10): RC143 - RC143. [Abstract] [Full Text] [PDF]
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R. Brown, A. Ollerstam, B. Johansson, O. Skott, S. Gebre-Medhin, B. Fredholm, and A. E. G. Persson Abolished tubuloglomerular feedback and increased plasma renin in adenosine A1 receptor-deficient mice Am J Physiol Regulatory Integrative Comp Physiol, November 1, 2001; 281(5): R1362 - R1367. [Abstract] [Full Text] [PDF]
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