The stimulatory action and the development of tolerance to caffeine is associated with alterations in gene expression in specific brain regions

We sought neurochemical correlates to the stimulatory action of caffeine in rats and to adaptations during development of tolerance. Acute intraperito neal injections of caffeine (7.5 mg/kg) increased locomotion and NGFI-A mRN A, a marker of neuronal activity, in the hippocampal area CA1, but decrease d 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 t o the stimulatory effect of a challenge with caffeine (7.5 mg/kg) and respo nded with a less pronounced decrease of NGFI-A mRNA in rostral striatum and nucleus accumbens. Metabolism of caffeine to its active metabolites was in creased in tolerant animals, but the total level of active metabolites in b rain was not significantly altered. Thus, there are changes in caffeine met abolism after long-term caffeine treatment, but they cannot explain develop ment of tolerance. Caffeine-tolerant animals had downregulated levels of adenosine A(2A) recep tors and the corresponding mRNA in rostral parts of striatum, but an increa sed expression of adenosine A(1) receptor mRNA in the lateral amygdala. No changes in mesencephalic tyrosine hydroxylase mRNA were found in caffeine-t olerant rats. Thus, we have identified neuronal pathways that are regulated by adenosine A(1) and/or A(2A) receptors and are targets for the stimulatory action of c affeine. Furthermore, adaptive changes in gene expression in these brain ar eas were associated with the development of locomotor tolerance to caffeine .