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Call For Papers: Computational Modeling of Physiological Systems

Uncovering multiple molecular targets for caffeine using a drug target validation strategy combining A_2A receptor knockout mice with microarray profiling

¹ Department of Neurology, Boston University School of Medicine
² Bioinformatics Program, Boston University, Boston, Massachusetts
³ Department of Biomedical Engineering, Boston University, Boston, Massachusetts
⁴ Department of Physiology and Pharmacology, Karolinska Institute, Stockholm, Sweden

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_2AR) 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_2AR gene deletion or by administering caffeine into A_2AR KO mice. Thus, A_2ARs 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_2ARs; 2) the second subset elicited by caffeine in WT as well as A_2AR KO mice; and 3) the third subset elicited by caffeine only in A_2AR 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_2AR 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_2AR, non-A_2AR (possibly A₁Rs and pathways associated with PDE and GABA_AR) 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.

adenosine A_2A receptor; striatum; phosphodiesterase