Effect of long term caffeine treatment on A1 and A2 adenosine receptor binding and on mRNA levels in rat brain

Abstract

The effect of long-term oral treatment with caffeine on A1 and A2 receptors in the rat brain was studied. Caffeine was added to the drinking water and the animals were sacrificed after a 12 day treatment period. The plasma caffeine concentration was close to 100 microM. A1 receptors were studied using quantitative autoradiography with [3H]cyclohexyladenosine (CHA). Caffeine treatment increased the number of A1 receptors in the CA3 subfield of the hippocampus from 337 to 393 fmol/mg with no change in KD (0.692 vs. 0.675 nM). A1 mRNA was measured using Northern blots and quantitative in situ hybridization. There was no increase in A1 mRNA. A2a receptors, located in dopamine rich regions of the rat brain, were studied with quantitative autoradiography using [3H]CGS 21680 as the ligand, and the A2a mRNA was determined using quantitative in situ hybridization. Caffeine treatment produced no significant change in either receptor number or mRNA, even though the apparent Bmax tended to increase from 322 +/- 8 to 352 +/- 8 fmol/mg. The results show that treatment with caffeine in a dose that causes tolerance to several effects of caffeine and increases some effects of adenosine analogues increases the number of A1 receptors without any change in A1 mRNA, suggesting that the adaptive changes are at a post-translational level. There were no significant changes in A2 receptors indicating that the two types are regulated differently and/or that the amount of endogenous agonist is sufficient to regulate A1, but not A2 receptors.

Biphasic changes in locomotor behavior and in expression of mRNA for NGFI-A and NGFI-B in rat striatum following acute caffeine administration

“…We and others have reported that a single injection of caffeine at doses between 50 and 100 mg/kg can upregulate expression of mRNA for the immediate early genes c-fos, jun B and c-&n (Nakajima et al, 1989;Johansson et al, 1993a;Svenningsson et al, 1995). This induction is followed by increased levels of mRNA for enkephalin and dynorphin in the same regions (Svenningsson et al, 1995, and own unpublished observations).…”

“…It is important to point out that, in contrast to the decrease in the expression of immediate early genes seen after low doses, which occurs mainly in striatopallidal neurons, the increase after higher doses occurs in both types of medium-sized spiny neurons (Johansson et al, 1993a;Svenningsson et al, 1995; this study). We recently found an inhibition of the caffeine-induced expression of mRNA for NGFI-A, and c-fos in caudate-putamen following pretreatment with NMDA receptor antagonists (Svenningsson et al, 1996).…”

“…The mRNA for adenosine A, receptors is, however, only weakly expressed in the striatum (Johansson et al, 1993a), suggesting that the striatal A, receptors may be localized to terminals of neurons whose cell bodies are elsewhere. Adenosine A,, receptors are enriched in the striatum (Parkinson and Fredholm, 1990) and so is the corresponding mRNA (Johansson et al, 1993a), indicating a localization to intrinsic neurons. Indeed the adenosine A,, receptors may be confined to pallidal-projecting GABAergic enkephalin-containing neurons, which also express dopamine D, receptors (Fink et al, 1992;Schiffmann et al, 1991).…”

“…Adenosine A, receptors are predominantly expressed in cerebral cortex, hippocampus, some thalamic nuclei and cerebellar cortex, but are also located in striatum (Fastbom et al, 1987). The mRNA for adenosine A, receptors is, however, only weakly expressed in the striatum (Johansson et al, 1993a), suggesting that the striatal A, receptors may be localized to terminals of neurons whose cell bodies are elsewhere. Adenosine A,, receptors are enriched in the striatum (Parkinson and Fredholm, 1990) and so is the corresponding mRNA (Johansson et al, 1993a), indicating a localization to intrinsic neurons.…”

Mice lacking the adenosine A1 receptor have normal spatial learning and plasticity in the CA1 region of the hippocampus, but they habituate more slowly

“…Adenosine A 1 receptors (A 1 Rs) are abundant in brain and a large proportion of these receptors are found on glutamatergic nerve endings, where they regulate transmitter release (Fredholm and Dunwiddie, 1988;Lupica et al, 1992;Johansson et al, 1993;Dunwiddie and Masino, 2001). The hippocampal formation is enriched with A 1 Rs (Fastbom et al, 1987;Svenningsson et al, 1997) and these receptors may be involved in the development and consolidation of longterm potentiation (LTP) (Arai et al, 1990;de Mendonca and Ribeiro, 1990;Alzheimer et al, 1991;Forghani and Krnjevic, 1995) and in induction of long-term depression (LTD) (de Mendonca et al, 1997;Bon and Garthwaite, 2002;Moore et al, 2003).…”