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I, Fredholm BB. Mice heterozygous for both A1 and A2A adenosine receptor genes show similarities to mice given long-term caffeine. J Appl Physiol 106: 631-639, 2009. First published November 26, 2008 doi:10.1152/japplphysiol.90971.2008.-Caffeine is believed to exert its stimulant effects by blocking A2A and A1 adenosine receptors (A2AR and A1R). Although a genetic knockout of A2AR eliminates effects of caffeine, the phenotype of the knockout animal does not resemble that of caffeine treatment. In this study we explored the possibility that a mere reduction of the number of A1Rs and A2ARs, achieved by deleting one of the two copies of the A1R and A2AR genes, would mimic some aspects of long-term caffeine ingestion. The A1R and A2AR double heterozygous (A1R-A2AR dHz) mice indeed had approximately one-half the number of A1R and A2AR, and there were little compensatory changes in A2B or A3 adenosine receptor (A2BR or A3R) expression. The ability of a stable adenosine analog to activate receptors was shifted to the right by caffeine and in A1R-A2AR dHz tissue. Caffeine (0.3 g/l in drinking water for 7-10 days) and A1R-A2AR dHz genotype increased locomotor activity (LA) and decreased heart rate without significantly influencing body temperature. The acute stimulatory effect of a single injection of caffeine was reduced in A1R-A2AR dHz mice and in mice treated long term with oral caffeine. Thus at least some aspects of long-term caffeine use can be mimicked by genetic manipulation of the A1R and A2AR. knockout; locomotor activity; tolerance; receptor binding; lipolysis CAFFEINE IS THE MOST WIDELY consumed psychoactive drug (15). It is generally believed that most of its actions in habitually consumed doses can be explained by its being an antagonist of adenosine receptors (12, 15). Since competitive antagonists are active if the receptors are occupied by an agonist, only adenosine receptors that are activated by endogenous adenosine under physiological conditions are likely targets for the effects of caffeine. Therefore, the focus has been on adenosine A 1 and A 2A receptors (A 1 R and A 2A R) (15), because these receptors where abundantly expressed are activated by endogenous adenosine levels. Indeed, it has been shown that some of the effects of caffeine are eliminated by knocking out the A 2A R (10, 20). However, the phenotype of the A 2A R knockout (KO) mouse is different from that of a caffeine-treated mouse. In doses commonly consumed by humans, caffeine (and its breakdown products) will bind to 25-50% of the A 1 R and A 2A R. Such blockade if continued for a long time may have functional consequences similar to a reduction in receptor number. Our group (2, 22) has previously shown that mice with only a single copy of the adenosine A 1 or A 2A gene have approximately one-half the number of receptors. Therefore, we hypothesize that mice that have a reduced number (rather than a complete elimination) of both A 1 Rs and A 2A Rs may show features of mice that are treated for a long time with caffeine, and subsequent...

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BackgroundThere are lingering concerns about caffeine consumption during pregnancy or the early postnatal period, partly because there may be long-lasting behavioral changes after caffeine exposure early in life.Methodology/Principal FindingsWe show that pregnant wild type (WT) mice given modest doses of caffeine (0.3 g/l in drinking water) gave birth to offspring that as adults exhibited increased locomotor activity in an open field. The offspring also responded to cocaine challenge with greater locomotor activity than mice not perinatally exposed to caffeine. We performed the same behavioral experiments on mice heterozygous for adenosine A1 receptor gene (A1RHz). In these mice signaling via adenosine A1 receptors is reduced to about the same degree as after modest consumption of caffeine. A1RHz mice had a behavioral profile similar to WT mice perinatally exposed to caffeine. Furthermore, it appeared that the mother's genotype, not offspring's, was critical for behavioral changes in adult offspring. Thus, if the mother partially lacked A1 receptors the offspring displayed more hyperactivity and responded more strongly to cocaine stimulation as adults than did mice of a WT mother, regardless of their genotype. This indicates that long-term behavioral alterations in the offspring result from the maternal effect of caffeine, and not a direct effect on fetus. WT offspring from WT mother but having a A1R Hz grandmother preserved higher locomotor response to cocaine.Conclusions/SignificanceWe suggest that perinatal caffeine, by acting on adenosine A1 receptors in the mother, causes long-lasting behavioral changes in the offspring that even manifest themselves in the second generation.