About 10 percent of American adults have struggled with substance use disorders (SUDs). In some SUDs, such as cocaine and methamphetamine (METH) use disorders, there are no approved medications. For other substances, such as alcohol, nicotine, and opioids, there are approved medications available, but relapse rates are high. It is highly desirable to develop improved treatments for SUDs. Recently reported studies have revealed an interesting role of ghrelin in drug abuse and award-relevant behaviors. Ghrelin, known as a 28 amino-acid peptide (GSSFLSPEHQKAQQRKESKKPPAKLQPR) acylated at Ser3 by a fatty acid, is produced in the stomach and travels to the brain through blood circulation. In the brain, ghrelin acts on ghrelin (or growth hormone secretagogue) receptor (GHSR) to stimulate the mesolimbic dopamine reward pathway and increase rewarding behaviors in rodents. Ghrelin receptor antagonism has been shown to attenuate METH-, amphetamine-, cocaine-, nicotine-, fentanyl-, morphine-, and alcohol-induced rewarding effects. For example, administration of a selective GHSR antagonist significantly and dose-dependently attenuated morphine-induced conditioned placed preference (CPP) and dopamine sensitization, and attenuated METH self-administration, tendency to relapse, and METH-induced CPP. In addition, pretreatment with a selective GHSR antagonist significantly and dose‐dependently reduced the manifestation of fentanyl‐CPP and reduced the fentanyl‐seeking/relapse‐like behavior in rats. In fact, GHSR antagonism is one of the NIDA’s 10 Most-Wanted targets for opioid user disorder medication development. On the other hand, GHSR possesses a naturally high constitutive activity (in the absence of ghrelin ligand) representing 50% of its maximal activity. Due to the ghrelin receptor’s diverse regulatory roles associated with its constitutive activity, GHSR antagonism could also result in unwanted adverse effects. Thus, alternative strategies targeting ghrelin itself could be a more interesting approach. 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 using ghrelin sequestering approaches. It is unknown whether any of the previously used approaches was able to decrease the ghrelin level significantly enough to attenuate the substance reward. We propose to develop and test an efficient ghrelin hydrolase which can be used as a safe and effective ghrelin modulator to attenuate substance rewarding effects as effective as a GHSR antagonist but without interacting with any brain receptors/transporters and to treat SUDs, including METH and opioid use disorders etc. Accomplishment of this investigation will determine whether ghrelin itself is a truly effective target and whether the specific ghrelin hydrolase as a ghrelin modulator is truly effective for treatment of SUDs. If the answers are all positive (as anticipated according to our preliminary data; see below), the effective ghrelin hydrolase (recombinant protein) to be developed and tested may also serve as a promising therapeutic candidate for treatment of SUDs.

Accomplishment of this investigation will validate a potentially promising, new target and may eventually lead to development of a novel therapeutic approach to treatment of substance use disorders.