Locating the neuronal targets for caffeine

Abstract

Caffeine is the most widely consumed of all psychoactive drugs. In doses that induce behavioral stimulation it acts primarily on adenosine A2A and possibly A1 receptors. Actions on the latter appear to be very much involved with regulation of the stimulatory glutamatergic input to several neuronal structures, including the striatum. Adenosine A2A receptors are found enriched on a subpopulation of GABAergic output neurons from the striatum, where they coexist with dopamine D2 receptors. The two receptors interact, both at the membrane level and by having opposing effects at the level of second messengers. Inhibition of adenosine A2A receptors by the selective antagonist SCH 58261 causes motor stimulation and a decrease in the expression of immediate early genes in these striatopallidal neurons. This effect is also clearly seen when dopamine D2 activation is blocked, either by preventing dopaminergic impulse flow or by receptor blockade. Thus, a tonic effect of endogenous adenosine is specifically antagonized by adenosine receptor antagonists such as caffeine. Despite a strictly delimited primary effect, secondary interactions between neurons lead to changes in the activity of several groups of neurons in interconnected networks. These changes likely underlie the behavioral effects of caffeine. Drug Dev. Res. 45:324–328, 1998. © 1998 Wiley‐Liss, Inc.

Molecular Dynamics Simulations Reveal Insights into Key Structural Elements of Adenosine Receptors

“…The use of adenosine itself in the treatment of certain arrhythmias and the anti-infarct effect of other adenosine agonists is mediated by the A 1 AR, while the A 2A AR is involved in vascular diseases such as hypertension or atherosclerosis . ARs are also involved in neural regulation in the central nervous system, as exemplified by the well-known AR antagonist caffeine . The recent discovery of A 2A AR–dopamine D 2 receptor heterodimers in ganglial neurons led to increased interest in the A 2A AR as a target for Alzheimer's disease …”

“…9 ARs are also involved in neural regulation in the central nervous system, as exemplified by the well-known AR antagonist caffeine. 10 The recent discovery of A 2A ARÀdopamine D 2 receptor heterodimers in ganglial neurons led to increased interest in the A 2A AR as a target for Alzheimer's disease. 11 Given the high degree of biomedical relevance of the AR family members, it is not difficult to understand the breakthrough that meant the release of the hA 2A AR crystal structure at a resolution of 2.6 Å.…”