Mice heterozygous for both A₁ and A_2A adenosine receptor genes show similarities to mice given long-term caffeine

Abstract

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...

Physiological roles of A1 and A2A adenosine receptors in regulating heart rate, body temperature, and locomotion as revealed using knockout mice and caffeine

“…The difference could be partially related to the difference between acute blockade and the life-long elimination of a receptor and perhaps also to the difference between eliminating the receptor and partially blocking it with a competitive antagonist. The latter possibility is supported by our recent finding that double heterozygous mice show increased LA (50).…”

International Union of Basic and Clinical Pharmacology. LXXXI. Nomenclature and Classification of Adenosine Receptors—An Update

“…Another reason for discrepancy is that drugs rarely achieve a complete blockade of an adenosine receptor for any length of time and complete elimination of a response and partial blockade may have very different consequences. Therefore, it is of interest that there are some examples in which heterozygous mice can be used to mimic phenotypes of long-term drug treatment (Björklund et al, 2008;Yang et al, 2009b).…”

Caffeine at Moderate Doses Can Inhibit Acupuncture-Induced Analgesia in a Mouse Model of Postoperative Pain

“…If all consumption resulted in caffeine intake, this would correspond to doses of *4 mg/kg/day or *70 mg/kg/day, using the caffeine concentration of 0.0015% or 0.03%, respectively. 11,25 Previous studies have related the dosage of 0.03% to moderate human dietary caffeine consumption. 11,25 Based on the average caffeine consumption in different countries described by Fredholm et al, 26 we noticed that an average of daily caffeine consumption in China is approximately twenty times lower than in Western countries (Table 1).…”