title: Uncovering multiple molecular targets for caffeine using a drug target validation strategy combining A 2A receptor knockout mice with microarray profiling.
abstract: Caffeine is the most widely consumed psychoactive substance and has complex pharmacological actions in brain. In this study, we employed a novel drug target validation strategy to uncover the multiple molecular targets of caffeine using combined A(2A) receptor (A(2A)R) knockouts (KO) and microarray profiling. Caffeine (10 mg/kg) elicited a distinct profile of striatal gene expression in WT mice compared with that by A(2A)R gene deletion or by administering caffeine into A(2A)R KO mice. Thus, A(2A)Rs are required but not sufficient to elicit the striatal gene expression by caffeine (10 mg/kg). Caffeine (50 mg/kg) induced complex expression patterns with three distinct sets of striatal genes: 1) one subset overlapped with those elicited by genetic deletion of A(2A)Rs; 2) the second subset elicited by caffeine in WT as well as A(2A)R KO mice; and 3) the third subset elicited by caffeine only in A(2A)R KO mice. Furthermore, striatal gene sets elicited by the phosphodiesterase (PDE) inhibitor rolipram and the GABA(A) receptor antagonist bicucullin, overlapped with the distinct subsets of striatal genes elicited by caffeine (50 mg/kg) administered to A(2A)R KO mice. Finally, Gene Set Enrichment Analysis reveals that adipocyte differentiation/insulin signaling is highly enriched in the striatal gene sets elicited by both low and high doses of caffeine. The identification of these distinct striatal gene populations and their corresponding multiple molecular targets, including A(2A)R, non-A(2A)R (possibly A(1)Rs and pathways associated with PDE and GABA(A)R) and their interactions, and the cellular pathways affected by low and high doses of caffeine, provides molecular insights into the acute pharmacological effects of caffeine in the brain.
authors.affiliation: Department of Neurology, Boston University School of Medicine, Boston, MA 02118, USA.
authors.forename: Liqun
authors.initials: L
authors.lastname: Yu
authors.forename: Joana E
authors.initials: JE
authors.lastname: Coelho
authors.forename: Xiaoling
authors.initials: X
authors.lastname: Zhang
authors.forename: Yutao
authors.initials: Y
authors.lastname: Fu
authors.forename: Abigail
authors.initials: A
authors.lastname: Tillman
authors.forename: Ulas
authors.initials: U
authors.lastname: Karaoz
authors.forename: Bertil B
authors.initials: BB
authors.lastname: Fredholm
authors.forename: Zhiping
authors.initials: Z
authors.lastname: Weng
authors.forename: Jiang-Fan
authors.initials: JF
authors.lastname: Chen
mesh_terms: D000818:Animals; D001640:Bicuculline / Q000494:pharmacology; D002110:Caffeine / Q000494:pharmacology*; D000697:Central Nervous System Stimulants / Q000494:pharmacology; D016000:Cluster Analysis; D004305:Dose-Response Relationship, Drug; D005260:Female; D018756:GABA Antagonists / Q000494:pharmacology; D020869:Gene Expression Profiling; D005786:Gene Expression Regulation / Q000187:drug effects; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D017072:Neostriatum / Q000187:drug effects / Q000378:metabolism; D020411:Oligonucleotide Array Sequence Analysis / Q000379:methods*; D010726:Phosphodiesterase Inhibitors / Q000494:pharmacology; D043705:Receptor, Adenosine A2A / Q000235:genetics / Q000502:physiology*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D020889:Rolipram / Q000494:pharmacology
chemical_list: D000697:Central Nervous System Stimulants; D018756:GABA Antagonists; D010726:Phosphodiesterase Inhibitors; D043705:Receptor, Adenosine A2A; D002110:Caffeine; D020889:Rolipram; D001640:Bicuculline