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Like other wake-promoting drugs (stimulants and modafinil), caffeine enhances dopamine (DA) signaling in the brain, which it does predominantly by antagonizing adenosine A<jats:sub>2A<\/jats:sub>receptors (A<jats:sub>2A<\/jats:sub>R). 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 [<jats:sup>11<\/jats:sup>C]raclopride (DA D<jats:sub>2<\/jats:sub>\/D<jats:sub>3<\/jats:sub>receptor radioligand sensitive to endogenous DA) to assess if caffeine increased DA release in striatum in 20 healthy controls. Caffeine (300\u2009mg p.o.) significantly increased the availability of D<jats:sub>2<\/jats:sub>\/D<jats:sub>3<\/jats:sub>receptors in putamen and ventral striatum, but not in caudate, when compared with placebo. In addition, caffeine-induced increases in D<jats:sub>2<\/jats:sub>\/D<jats:sub>3<\/jats:sub>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 D<jats:sub>2<\/jats:sub>\/D<jats:sub>3<\/jats:sub>receptors, which indicates that caffeine does not increase DA in the striatum for this would have decreased D<jats:sub>2<\/jats:sub>\/D<jats:sub>3<\/jats:sub>receptor availability. Instead, we interpret our findings to reflect an increase in D<jats:sub>2<\/jats:sub>\/D<jats:sub>3<\/jats:sub>receptor levels in striatum with caffeine (or changes in affinity). The association between increases in D<jats:sub>2<\/jats:sub>\/D<jats:sub>3<\/jats:sub>receptor availability in ventral striatum and alertness suggests that caffeine might enhance arousal, in part, by upregulating D<jats:sub>2<\/jats:sub>\/D<jats:sub>3<\/jats:sub>receptors.<\/jats:p>","DOI":"10.1038\/tp.2015.46","type":"journal-article","created":{"date-parts":[[2015,4,14]],"date-time":"2015-04-14T13:42:52Z","timestamp":1429018972000},"page":"e549-e549","update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":147,"title":["Caffeine increases striatal dopamine D2\/D3 receptor availability in the human brain"],"prefix":"10.1038","volume":"5","author":[{"given":"N D","family":"Volkow","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"G-J","family":"Wang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"J","family":"Logan","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"D","family":"Alexoff","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"J S","family":"Fowler","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"P K","family":"Thanos","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"C","family":"Wong","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"V","family":"Casado","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"S","family":"Ferre","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"D","family":"Tomasi","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2015,4,14]]},"reference":[{"key":"BFtp201546_CR1","doi-asserted-by":"publisher","first-page":"136","DOI":"10.1016\/j.fct.2013.10.042","volume":"63","author":"DC Mitchell","year":"2014","unstructured":"Mitchell DC, Knight CA, Hockenberry J, Teplansky R, Hartman TJ . 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