Genome-Wide Expression Profiles Drive Discovery of Novel Compounds that Reduce Binge Drinking in Mice

Laura B. Ferguson, Angela Ozburn, Igor Ponomarev, Pamela Metten, Matthew Reilly, John Jr Crabbe, R. Adron Harris, R. Dayne Mayfield

Research output: Contribution to journalArticle

5 Citations (Scopus)

Abstract

Transcriptome-based drug discovery has identified new treatments for some complex diseases, but has not been applied to alcohol use disorder (AUD) or other psychiatric diseases, where there is a critical need for improved pharmacotherapies. High Drinking in the Dark (HDID-1) mice are a genetic model of AUD risk that have been selectively bred (from the HS/Npt line) to achieve intoxicating blood alcohol levels (BALs) after binge-like drinking. We compared brain gene expression of HDID-1 and HS/Npt mice, to determine a molecular signature for genetic risk for high intensity, binge-like drinking. Using multiple computational methods, we queried LINCS-L1000 (Library of Integrated Network-Based Cellular Signatures), a database containing gene expression signatures of thousands of compounds, to predict candidate drugs with the greatest potential to decrease alcohol consumption. Our analyses predicted novel compounds for testing, many with anti-inflammatory properties, providing further support for a neuroimmune mechanism of excessive alcohol drinking. We validated the top 2 candidates in vivo as a proof-of-concept. Terreic acid (a Bruton's tyrosine kinase inhibitor) and pergolide (a dopamine and serotonin receptor agonist) robustly reduced alcohol intake and BALs in HDID-1 mice, providing the first evidence for transcriptome-based drug discovery to target an addiction trait. Effective drug treatments for many psychiatric diseases are lacking, and the emerging tools and approaches outlined here offer researchers studying complex diseases renewed opportunities to discover new or repurpose existing compounds and expedite treatment options.

Original languageEnglish (US)
Pages (from-to)1257-1266
Number of pages10
JournalNeuropsychopharmacology
Volume43
Issue number6
DOIs
StatePublished - May 1 2018

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Binge Drinking
Transcriptome
Genome
Alcohols
Drug Discovery
Alcohol Drinking
Psychiatry
Neuroimmunomodulation
Pergolide
Serotonin Receptor Agonists
Genetic Models
Dopamine Agonists
Pharmaceutical Preparations
Drinking
Libraries
Molecular Biology
Anti-Inflammatory Agents
Therapeutics
Research Personnel
Databases

ASJC Scopus subject areas

  • Pharmacology
  • Psychiatry and Mental health

Cite this

Genome-Wide Expression Profiles Drive Discovery of Novel Compounds that Reduce Binge Drinking in Mice. / Ferguson, Laura B.; Ozburn, Angela; Ponomarev, Igor; Metten, Pamela; Reilly, Matthew; Crabbe, John Jr; Harris, R. Adron; Mayfield, R. Dayne.

In: Neuropsychopharmacology, Vol. 43, No. 6, 01.05.2018, p. 1257-1266.

Research output: Contribution to journalArticle

Ferguson, Laura B. ; Ozburn, Angela ; Ponomarev, Igor ; Metten, Pamela ; Reilly, Matthew ; Crabbe, John Jr ; Harris, R. Adron ; Mayfield, R. Dayne. / Genome-Wide Expression Profiles Drive Discovery of Novel Compounds that Reduce Binge Drinking in Mice. In: Neuropsychopharmacology. 2018 ; Vol. 43, No. 6. pp. 1257-1266.
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