Plasma butyrylcholinesterase regulates ghrelin to control aggression

Vicky Ping Chen, Yang Gao, Liyi Geng, Robin J. Parks, Yuan Ping Pang, Stephen Brimijoin

Research output: Contribution to journalArticle

57 Scopus citations

Abstract

Ongoing mouse studies of a proposed therapy for cocaine abuse based on viral gene transfer of butyrylcholinesterase (BChE) mutated for accelerated cocaine hydrolysis have yielded surprising effects on aggression. Further investigation has linked these effects to a reduction in circulating ghrelin, driven by BChE at levels ?100-fold above normal. Tests with human BChE showed ready ghrelin hydrolysis at physiologic concentrations, and multiple low-mass molecular dynamics simulations revealed that ghrelin's first five residues fit sterically and electrostatically into BChE's active site. Consistent with in vitro results, male BALB/c mice with high plasma BChE after gene transfer exhibited sharply reduced plasma ghrelin. Unexpectedly, such animals fought less, both spontaneously and in a resident/intruder provocation model. One mutant BChE was found to be deficient in ghrelin hydrolysis. BALB/c mice transduced with this variant retained normal plasma ghrelin levels and did not differ from untreated controls in the aggression model. In contrast, C57BL/6 mice with BChE gene deletion exhibited increased ghrelin and fought more readily than wild-type animals. Collectively, these findings indicate that BChE-catalyzed ghrelin hydrolysis influences mouse aggression and social stress, with potential implications for humans.

Original languageEnglish (US)
Pages (from-to)2251-2256
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume112
Issue number7
DOIs
StatePublished - Feb 17 2015

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Keywords

  • Aggression
  • BChE
  • Ghrelin
  • Mice
  • Viral vector

ASJC Scopus subject areas

  • General

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