Chronic caffeine ingestion sensitizes the A1 adenosine receptor-adenylate cyclase system in rat cerebral cortex.

Abstract

membranes to 190±10 fmol/mg protein in treated membranes (P = 0.01). These data indicate that the adenosine receptor antagonist, caffeine, induces a compensatory sensitization of the Al receptor-adenylate cyclase system and downregulation of jBadrenergic receptors, and provides a molecular mechanism for the caffeine withdrawal syndrome. IntroductionThe daily consumption of caffeine is estimated at 200 mg per adult (1, 2), approximately equivalent to two cups of coffee/d. Acute caffeine intake is associated with arrhythmias (3), increased heart rate (4, 5) and stroke volume (6), altered blood pressure (5), sleeplessness (7), and other physiologic and behavioral alterations. The physiologic and metabolic effects of chronic caffeine use are less well-documented (8-1 1) and little is known about the biochemical effects of chronic caffeine ingestion.Although the pharmacologic action of the methylxanthines Address reprint requests to Dr. Stiles,

Locomotor activity in mice during chronic treatment with caffeine and withdrawal

“…14). Such a heightened response to adenosine analogs is consonant with the known upregulation of A 1 and A 2 adenosine receptors in the brain of caffeine-treated rodents (7,13,16,20,21,35) and in the ability of either A 1 or A 2 receptors to subserve behavioral depression in mice (38). In only one study (24) did chronic treatment of rats with caffeine not cause an increase in brain A 1 receptors.…”

“…Adenosine analogs appear capable of eliciting behavioral depression through activation of either A 1 or A 2 adenosine receptors (37,38). Indeed, chronic ingestion of caffeine results in an upregulation in levels of adenosine receptors (7,16,20,21,35). Remarkably, caffeine and other xanthines are more potent in reversing the depressant effects of adenosine analogs in vivo than in causing behavioral stimulation of locomotor exploratory activity when administered alone (27).…”

“…The mechanism(s) underlying such tolerance, as well as the withdrawal syndrome, are not well understood. The increase of levels of adenosine receptors after chronic caffeine (7,16,20,21,35) suggests upregulation of adenosine receptor-mediated functions as a basis for caffeine tolerance. A number of points argue against such a simple explanation: First, in rats the tolerance to caffeine can appear insurmountable (16); second, there are no clear precedents for loss of antagonist potency after chronic administration of a competitive receptor antagonist.…”

Chronic caffeine alters the density of adenosine, adrenergic, cholinergic, GABA, and serotonin receptors and calcium channels in mouse brain

“…The effects of chronic caffeine on other central receptors has received less attention. β-Adrenergic receptors appear down-regulated, while α-adrenergic receptors appear unchanged (Goldberg et al, 1982;Green and Stiles, 1986). Caffeine does alter turnover of not only norepinephrine, but also of dopamine and serotonin (Berkowitz et al, 1970;Berkowitz and Spector, 1971;Corrodi et al, 1972;Hadfield and Milio, 1989).…”

“…Blockade of central adenosine receptors resulting in an up-regulation of adenosine receptors has received attention as one explanation of the chronic effects of caffeine. Chronic treatment with caffeine does result in an apparent up-regulation of A 1 adenosine receptors in rodents (Fredholm, 1982;Boulenger et al, 1983;Wu and Coffin, 1984;Green and Stiles, 1986;Zielke and Zielke, 1987;Hawkins et al, 1988;Ramkumar et al, 1988;Daval et al, 1989;Rudolphi et al, 1989; see also references in Nehlig et al, 1992;Daly, 1993), and an enhanced sensitivity to behavioral effects of adenosine analogs (Ahlijanian et al, 1986;Nikodijević et al, 1993). The effects of chronic caffeine on other central receptors has received less attention.…”