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.

Significance of preoperative butyrylcholinesterase as an independent predictor of biochemical recurrence-free survival in patients with prostate cancer treated with radical prostatectomy

“…Plasma BChE levels have been found to be decreased in advanced cancer patients with or without hepatic involvement, despite having other normal liver function tests [19]. Recently, Chen et al reported that circulating BChE has a large impact on aggressive behavior in mice that is attributable to its ability to inactivate ghrelin [20]. In addition, circulating ghrelin concentrations are negatively correlated with body mass index in humans [21].…”

Long-Term Blockade of Cocaine Self-Administration and Locomotor Activation in Rats by an Adenoviral Vector-Delivered Cocaine Hydrolase

“…Chen et al (2015) recently found that elevated levels of native BChE or CocH also reduced aggression in mice, tracing such an effect to enzyme-driven inactivation of plasma ghrelin. This peptide hormone is better known for its role in hunger and feeding (Kojima et al, 1999), but it also plays a role in stress and anxiety (Carlini et al, 2002).…”

Single-cell transcriptomes identify human islet cell signatures and reveal cell-type–specific expression changes in type 2 diabetes

“…Delta cells also specifically expressed BCHE, which encodes butyrylcholinesterase. BCHE catalyzes the breakdown of acetylcholine and ghrelin (Chen et al 2015), thus providing a mechanism for delta cells to exert local inhibition of islet-influencing endocrine signals. PP/gamma cell-specific transcriptomes included CTD-2008P7.8, a lincRNA of unknown function; CNTNAP5, a member Table S9).…”