Regulation of ethanol-related behavior and ethanol metabolism by the Corazonin neurons and Corazonin receptor in Drosophila melanogaster

PLoS One. 2014 Jan 28;9(1):e87062. doi: 10.1371/journal.pone.0087062. eCollection 2014.

Abstract

Impaired ethanol metabolism can lead to various alcohol-related health problems. Key enzymes in ethanol metabolism are alcohol dehydrogenase (ADH) and aldehyde dehydrogenase (ALDH); however, neuroendocrine pathways that regulate the activities of these enzymes are largely unexplored. Here we identified a neuroendocrine system involving Corazonin (Crz) neuropeptide and its receptor (CrzR) as important physiological regulators of ethanol metabolism in Drosophila. Crz-cell deficient (Crz-CD) flies displayed significantly delayed recovery from ethanol-induced sedation that we refer to as hangover-like phenotype. Newly generated mutant lacking Crz Receptor (CrzR(01) ) and CrzR-knockdown flies showed even more severe hangover-like phenotype, which is causally associated with fast accumulation of acetaldehyde in the CrzR(01) mutant following ethanol exposure. Higher levels of acetaldehyde are likely due to 30% reduced ALDH activity in the mutants. Moreover, increased ADH activity was found in the CrzR(01) mutant, but not in the Crz-CD flies. Quantitative RT-PCR revealed transcriptional upregulation of Adh gene in the CrzR(01) . Transgenic inhibition of cyclic AMP-dependent protein kinase (PKA) also results in significantly increased ADH activity and Adh mRNA levels, indicating PKA-dependent transcriptional regulation of Adh by CrzR. Furthermore, inhibition of PKA or cAMP response element binding protein (CREB) in CrzR cells leads to comparable hangover-like phenotype to the CrzR(01) mutant. These findings suggest that CrzR-associated signaling pathway is critical for ethanol detoxification via Crz-dependent regulation of ALDH activity and Crz-independent transcriptional regulation of ADH. Our study provides new insights into the neuroendocrine-associated ethanol-related behavior and metabolism.

Publication types

  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Acetaldehyde / metabolism
  • Alcohol Dehydrogenase / genetics
  • Alcohol Dehydrogenase / metabolism
  • Aldehyde Dehydrogenase / metabolism
  • Alleles
  • Animals
  • Cyclic AMP-Dependent Protein Kinases / metabolism
  • Drosophila Proteins / metabolism*
  • Drosophila melanogaster / drug effects
  • Drosophila melanogaster / enzymology
  • Drosophila melanogaster / metabolism*
  • Ethanol / metabolism*
  • Ethanol / pharmacology
  • Genes, Reporter
  • Male
  • Mutation / genetics
  • Neurons / drug effects
  • Neurons / metabolism*
  • Neuropeptides / metabolism*
  • Phenotype
  • RNA, Messenger / genetics
  • RNA, Messenger / metabolism
  • Receptors, Neuropeptide / metabolism*
  • Transcription, Genetic

Substances

  • Crz protein, Drosophila
  • Drosophila Proteins
  • Neuropeptides
  • RNA, Messenger
  • Receptors, Neuropeptide
  • corazonin receptor
  • Ethanol
  • Alcohol Dehydrogenase
  • Aldehyde Dehydrogenase
  • Cyclic AMP-Dependent Protein Kinases
  • Acetaldehyde

Grant support

This work was supported by National Science Foundation (NSF) grants (IOS-0919797, IBN-0133538) (http://www.nsf.gov/) and a Fite fellowship from BCMB (K.S.) (http://web.bio.utk.edu/bcmb/grad/financial_support/advanced.html). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.