Grants and Contracts Details
Description
With currently available medications for opioid use disorder (OUD), the relapse rate is very high. Further, co-
use of an opioid and a stimulant, such as methamphetamine (METH), undermines success in treatment for OUD.
It is highly desired to develop novel therapeutic options for treatment of OUDs including polysubstance use
disorders (PSUDs). Recently reported studies have revealed an interesting role of ghrelin in drug abuse and
award-relevant behaviors. Ghrelin is known as a “growth-hormone-releasing acylated peptide from stomach”, a
28 amino-acid peptide with the third residue (Ser3) acylated by n-octanoic acid. Ghrelin is produced in the
stomach, travels to the brain through blood circulation, and acts on ghrelin (or growth hormone secretagogue)
receptor (GHSR) to stimulate the mesolimbic dopamine reward pathway and increase rewarding behaviors in
rodents. GHSR antagonism has been shown to attenuate rewarding effects induced by various substances
including METH, amphetamine, fentanyl, morphine, heroin, cocaine, nicotine, and alcohol. For example,
administration of a selective GHSR antagonist significantly reduced the fentanyl-seeking/relapse-like behavior
in rats. On the other hand, GHSR has diverse regulatory roles associated with its constitutive activity (the activity
in the absence of ghrelin ligand) and, hence, GHSR antagonism could also result in unwanted adverse effects.
Thus, alternative strategies targeting ghrelin itself could be more interesting. However, whether targeting ghrelin
itself would be effective to attenuate the drug rewarding effects remains controversial in literature as ghrelin
levels before and after treatment were not measured in previous animal studies targeting ghrelin itself. It is
unclear whether any of the previously used approaches was able to decrease the ghrelin level significantly
enough to attenuate the substance reward. We propose to use our recently identified ghrelin deacylase (a mutant
of human butyrylcholinesterase or BChE) as a safe and effective ghrelin modulator to attenuate substance
rewarding effects. Such a ghrelin modulator is expected to be as effective as a GHSR antagonist in treatment of
substance use disorders (SUDs) including polysubstance use disorders (PSUDs), but without interacting with
any brain receptors/transporters. Specifically, in this investigation, we will first evaluate the BChE mutant for its
in vivo potency in modulating ghrelin and attenuating the rewarding and reinforcing effects of representative
opioids (fentanyl and heroin) and their combinations with METH in various rodent models. Then, we will design
and discover a new BChE mutant as a more potent ghrelin deacylase with further improved catalytic activity for
ghrelin diacylation, develop its long-acting fusion protein form, and examine the long-term in vivo effects of the
long-acting ghrelin deacylase. Accomplishment of this investigation will determine whether ghrelin itself is a truly
effective target and whether a potent ghrelin deacylase as a ghrelin modulator is truly effective for treatment of
PSUDs. If the answers are all positive, the most effective ghrelin deacylase (recombinant protein) to be tested
and developed may also serve as a promising therapeutic candidate for treatment of PSUDs.
Status | Active |
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Effective start/end date | 7/1/22 → 6/30/25 |
Funding
- National Institute on Drug Abuse: $1,700,947.00
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