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

Authors: N D Volkow et al. (2015)

Link: https://doi.org/10.1038/tp.2015.46

Background Information:

Caffeine is the world’s most commonly consumed psychoactive substance, often used to boost alertness and reduce tiredness. Its stimulating effects are similar to those of drugs like amphetamines or modafinil, which directly increase dopamine in the brain. However, caffeine doesn’t block dopamine transporters; instead, it primarily acts by blocking specific adenosine receptors (A₂A), which normally inhibit dopamine activity. These adenosine receptors are often found attached to dopamine D₂/D₃ receptors in the brain’s striatum, a key region for movement and reward. Animal studies have suggested that by blocking adenosine, caffeine might enhance dopamine signaling—either by increasing dopamine release or by affecting dopamine receptors—but whether this holds true for typical human caffeine consumption remained unclear. The article delves into the intricate role of dopamine in learning, motivation, and addiction. The authors emphasize that addiction is a learned behavior, where repeated exposure to addictive substances reinforces certain neural pathways, leading to compulsive behaviors. This paper provides a comprehensive understanding of the neurobiological mechanisms underlying addiction, offering valuable perspectives for both clinical and public health approaches to addiction prevention and treatment.

Purpose of the Study:

The researchers wanted to find out whether drinking a normal amount of caffeine (about 300 mg, roughly 2–3 cups of coffee) raises dopamine levels in the human brain’s striatum, or instead increases dopamine D₂/D₃ receptor availability. Measuring receptor availability can help distinguish between genuine dopamine release (which would reduce receptor availability) and other mechanisms like increased number or sensitivity of receptors. The study also explored whether any changes in receptor availability were linked to increased feelings of alertness after caffeine consumption.

Methods and Data Analysis:

Twenty healthy adult volunteers took part in a double-session study with two phases: one after taking 300 mg of caffeine and another after a placebo. Around 30 minutes after consumption—when caffeine effects peak—they underwent PET scans with [¹¹C]raclopride, a tracer that binds to dopamine D₂/D₃ receptors and is sensitive to the brain’s own dopamine levels. The researchers then measured binding potential in three regions of the striatum: putamen, ventral striatum, and caudate. A lower tracer binding would reflect increased dopamine release (displacing the tracer), while unchanged or increased binding would reflect other effects like receptor level changes. Subjective alertness was also recorded during both sessions.

Key Findings and Conclusions:

Contrary to raising dopamine levels, caffeine did not reduce tracer binding; instead it increased D₂/D₃ receptor availability in the putamen and ventral striatum, but not the caudate. This suggests that caffeine does not increase dopamine release at these normal doses. The researchers propose that caffeine may upregulate receptor quantity or alter receptor binding strength. Further, participants who showed larger increases in receptor availability in the ventral striatum also reported feeling more alert. This indicates that caffeine’s energizing effect may stem from boosting dopamine receptor signaling rather than dopamine release.

Applications & Limitations:

This study offers a fresh insight into how everyday caffeine consumption improves alertness—not by boosting dopamine directly, but by making dopamine receptors more available or sensitive. This has broader implications for understanding how caffeine enhances cognition and could open avenues for developing drugs that modulate these receptors. However, the study had a small sample size (20 people) and didn’t measure other related chemicals like adrenaline. It also didn’t clarify whether the change in receptor availability is short-term or if regular caffeine intake increases it long-term. Future studies are needed to explore how these findings might apply to people with sleep disorders, cognitive decline, or to chronic caffeine users.