Validation of Ghrelin Hydrolysis as an Effective Approach to Treatment of Substance Use Disorders

Validation of ghrelin hydrolysis as an effective approach to treatment of substance use disorders 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, 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 alcohol-, amphetamine-, cocaine-, nicotine- , morphine-, and METH-induced rewarding effects. For example, administration of a selective GHSR1A antagonist significantly and dose-dependently attenuated morphine-induced conditioned placed preference (CPP) and dopamine sensitization, and also attenuated METH self-administration, tendency to relapse, and METH-induced CPP. In fact, GHSR antagonism is one of the NIDA’s 10 Most-Wanted targets for opioid user disorder medication development. On the other hand, due to the ghrelin receptor’s diverse regulatory roles, 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 negative modulator to attenuate substance rewarding effects and 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 approach as a ghrelin negative 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.