title: Plasma butyrylcholinesterase regulates ghrelin to control aggression.
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.
authors: Department of Molecular Pharmacology and Experimental Therapeutics, Mayo Clinic, Rochester, MN 55905; Kogod Center on Aging, Mayo Clinic, Rochester, MN 55905; and.
authors: Vicky Ping
authors: VP
authors: Chen
authors: Department of Molecular Pharmacology and Experimental Therapeutics, Mayo Clinic, Rochester, MN 55905; Kogod Center on Aging, Mayo Clinic, Rochester, MN 55905; and.
authors: Yang
authors: Y
authors: Gao
authors: Department of Molecular Pharmacology and Experimental Therapeutics, Mayo Clinic, Rochester, MN 55905; Kogod Center on Aging, Mayo Clinic, Rochester, MN 55905; and.
authors: Liyi
authors: L
authors: Geng
authors: Ottawa Hospital Research Institute, Ottawa, ON K1Y 4E9, Canada.
authors: Robin J
authors: RJ
authors: Parks
authors: Department of Molecular Pharmacology and Experimental Therapeutics, Mayo Clinic, Rochester, MN 55905;
authors: Yuan-Ping
authors: YP
authors: Pang
authors: Department of Molecular Pharmacology and Experimental Therapeutics, Mayo Clinic, Rochester, MN 55905; Kogod Center on Aging, Mayo Clinic, Rochester, MN 55905; and brimijoi@mayo.edu.
authors: Stephen
authors: S
authors: Brimijoin
mesh_terms: D000374:Aggression; D000818:Animals; D002091:Butyrylcholinesterase / Q000097:blood*; D054439:Ghrelin / Q000502:physiology*; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C
chemical_list: D054439:Ghrelin; D002091:Butyrylcholinesterase
keywords: BChE; aggression; ghrelin; mice; viral vector
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