Caffeine increases striatal dopamine D2/D3 receptor availability in the human brain.

N D Volkow,D Tomasi,G-J Wang,D Alexoff,J S Fowler,J Logan,C Wong,S Ferre,P K Thanos,V Casado

doi:10.1038/tp.2015.46

Abstract

Caffeine, the most widely consumed psychoactive substance in the world, is used to promote wakefulness and enhance alertness. Like other wake-promoting drugs (stimulants and modafinil), caffeine enhances dopamine (DA) signaling in the brain, which it does predominantly by antagonizing adenosine A2A receptors (A2AR). However, it is unclear if caffeine, at the doses consumed by humans, increases DA release or whether it modulates the functions of postsynaptic DA receptors through its interaction with adenosine receptors, which modulate them. We used positron emission tomography and [11C]raclopride (DA D2/D3 receptor radioligand sensitive to endogenous DA) to assess if caffeine increased DA release in striatum in 20 healthy controls. Caffeine (300 mg p.o.) significantly increased the availability of D2/D3 receptors in putamen and ventral striatum, but not in caudate, when compared with placebo. In addition, caffeine-induced increases in D2/D3 receptor availability in the ventral striatum were associated with caffeine-induced increases in alertness. Our findings indicate that in the human brain, caffeine, at doses typically consumed, increases the availability of DA D2/D3 receptors, which indicates that caffeine does not increase DA in the striatum for this would have decreased D2/D3 receptor availability. Instead, we interpret our findings to reflect an increase in D2/D3 receptor levels in striatum with caffeine (or changes in affinity). The association between increases in D2/D3 receptor availability in ventral striatum and alertness suggests that caffeine might enhance arousal, in part, by upregulating D2/D3 receptors.

Highlights

Caffeine is the most widely consumed psychoactive substance.[1]
We show that caffeine increases D2 and D3 receptors (D2/D3R) availability in striatum in a group of healthy controls with low levels of daily caffeine intake
These findings are consistent with findings from a prior positron emission tomography (PET) [11C]raclopride study done in a small group of subjects that reported increases in D2/D3R availability in striatum with caffeine (200 mg).[24]

Summary

Introduction

Caffeine is the most widely consumed psychoactive substance.[1] Its behavioral arousing pharmacological effects are similar to those of stimulant drugs (amphetamine and methylphenidate) and modafinil, which are drugs that increase dopamine (DA) signaling by blocking DA transporters and/or enhancing DA release from the terminals.[2,3,4] The DA-enhancing effects of these drugs underlie their arousing[5,6] and reinforcing effects.[7,8,9,10] In contrast, preclinical studies indicate that caffeine’s pharmacological effects are mediated by its antagonism of adenosine receptors (A1 and A2A subtypes).[11] In particular, its antagonism of A2A receptors (A2AR) in striatum has been implicated in its dopaminergic effects.[12] caffeine-induced increases in locomotor activity[13] and arousal[14] appear to be mediated by A2AR as they are absent in A2A R knockout mice, and silencing the expression of A2AR with shorthairpin RNA in the nucleus accumbens interferes with caffeine’s effects on wakefulness.[15]

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Conclusion