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The Journal of Neuroscience, May 15, 1999, 19(10):4011-4022

The Stimulatory Action and the Development of Tolerance to Caffeine Is Associated with Alterations in Gene Expression in Specific Brain Regions

Per Svenningsson, George G. Nomikos, and Bertil B. Fredholm

Section of Molecular Neuropharmacology, Department of Physiology and Pharmacology, Karolinska Institutet, 17177 Stockholm, Sweden

We sought neurochemical correlates to the stimulatory action of caffeine in rats and to adaptations during development of tolerance. Acute intraperitoneal injections of caffeine (7.5 mg/kg) increased locomotion and NGFI-A mRNA, a marker of neuronal activity, in the hippocampal area CA1, but decreased NGFI-A mRNA in rostral striatum and nucleus accumbens. Rats that received caffeine (0.3 gm/l) in their drinking water for 14 d developed tolerance to the stimulatory effect of a challenge with caffeine (7.5 mg/kg) and responded with a less pronounced decrease of NGFI-A mRNA in rostral striatum and nucleus accumbens. Metabolism of caffeine to its active metabolites was increased in tolerant animals, but the total level of active metabolites in brain was not significantly altered. Thus, there are changes in caffeine metabolism after long-term caffeine treatment, but they cannot explain development of tolerance.

Caffeine-tolerant animals had downregulated levels of adenosine A_2A receptors and the corresponding mRNA in rostral parts of striatum, but an increased expression of adenosine A₁ receptor mRNA in the lateral amygdala. No changes in mesencephalic tyrosine hydroxylase mRNA were found in caffeine-tolerant rats.

Thus, we have identified neuronal pathways that are regulated by adenosine A₁ and/or A_2A receptors and are targets for the stimulatory action of caffeine. Furthermore, adaptive changes in gene expression in these brain areas were associated with the development of locomotor tolerance to caffeine.

Key words: caffeine; methylxanthines; adenosine receptors; immediate early genes; striatum; drug tolerance; locomotion; in situ hybridization

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Copyright © 1999 Society for Neuroscience  0270-6474/99/19104011-12$05.00/0

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