Title

Uncovering multiple molecular targets for caffeine using a drug target validation strategy combining A 2A receptor knockout mice with microarray profiling

UMMS Affiliation

Department of Biochemistry and Molecular Pharmacology; Program in Bioinformatics and Integrative Biology

Date

5-13-2009

Document Type

Article

Medical Subject Headings

Animals; Bicuculline; Caffeine; Central Nervous System Stimulants; Cluster Analysis; Dose-Response Relationship, Drug; Female; GABA Antagonists; *Gene Expression Profiling; Gene Expression Regulation; Male; Mice; Mice, Knockout; Neostriatum; Oligonucleotide Array Sequence Analysis; Phosphodiesterase Inhibitors; Receptor, Adenosine A2A; Reverse Transcriptase Polymerase Chain Reaction; Rolipram

Disciplines

Bioinformatics | Computational Biology | Genetics and Genomics | Molecular Biology

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.

Rights and Permissions

Citation: Physiol Genomics. 2009 May 13;37(3):199-210. doi: 10.1152/physiolgenomics.90353.2008 Link to article on publisher's site

Comments

At the time of publication, Zhiping Weng was not yet affiliated with the University of Massachusetts Medical School.

Related Resources

Link to Article in PubMed