Selective Activation of Striatal NGF-TrkA/p75NTR/ MAPK Intracellular Signaling in Rats That Show Suppression of Methamphetamine Intake 30 Days following Drug Abstinence

Study Authors Mary R. Lee, Lisa A. Farinelli, Mehdi Farokhnia and Lorenzo Leggio

Featured Paper of the Month – October 2018.

Understanding the neurobiological substrates of excessive alcohol consumption may substantially facilitate efforts to develop better treatments. The cross-talk between the gastrointestinal and central nervous systems, often referred to as the gut–brain axis, is a promising yet underexplored domain in this regard. Ghrelin is a hormone primarily produced by the stomach and known for its role in increasing appetite and food intake (the “hunger hormone”). Recent animal and human studies suggest that ghrelin may also be involved in alcohol-seeking behaviors. In rodent experiments, blocking the ghrelin receptor suppresses alcohol seeking and consumption. In a series of preclinical and clinical experiments, NIDA/NIAAA scientists investigated a novel drug that blocks the ghrelin receptor in a population of alcohol-dependent heavy drinking individuals. The main goal of this study was to assess the safety of this new medication when co-administered with alcohol. First, experiments were performed in rats and indicated no safety concerns. Then, the NIDA/NIAAA team moved to a small controlled human study where this novel medication and alcohol were co-administered to heavy alcohol drinkers. Consistent with the rat experiments, the human study indicated the safety of the drug, with no evident drug-alcohol interactions. Very preliminary results from the human study also indicated that this novel medication might reduce cravings for alcohol and food. These findings support the notion that the ghrelin system may be further examined as a novel treatment target for addictive disorders.

Publication Information

Lee, Mary R; Tapocik, Jenica D; Ghareeb, Mwlod; Schwandt, Melanie L; Dias, Alexandra A; Le, April N; Cobbina, Enoch; Farinelli, Lisa A; Bouhlal, Sofia; Farokhnia, Mehdi; Heilig, Markus; Akhlaghi, Fatemeh; Leggio, Lorenzo

The novel ghrelin receptor inverse agonist PF-5190457 administered with alcohol: preclinical safety experiments and a phase 1b human laboratory study. Journal Article

In: Mol Psychiatry, 2020, ISSN: 1476-5578 (Electronic); 1359-4184 (Linking).

Abstract | Links

@article{Lee:2018aa,

title = {The novel ghrelin receptor inverse agonist PF-5190457 administered with alcohol: preclinical safety experiments and a phase 1b human laboratory study.},

author = {Mary R Lee and Jenica D Tapocik and Mwlod Ghareeb and Melanie L Schwandt and Alexandra A Dias and April N Le and Enoch Cobbina and Lisa A Farinelli and Sofia Bouhlal and Mehdi Farokhnia and Markus Heilig and Fatemeh Akhlaghi and Lorenzo Leggio},

url = {https://www.ncbi.nlm.nih.gov/pubmed/29728704},

doi = {10.1038/s41380-018-0064-y},

issn = {1476-5578 (Electronic); 1359-4184 (Linking)},

year  = {2020},

date = {2020-05-04},

urldate = {2020-05-04},

journal = {Mol Psychiatry},

address = {Section on Clinical Psychoneuroendocrinology and Neuropsychopharmacology, National Institute on Alcohol Abuse and Alcoholism and National Institute on Drug Abuse, National Institutes of Health, Bethesda, MD, USA.},

abstract = {Rodent studies indicate that ghrelin receptor blockade reduces alcohol consumption. However, no ghrelin receptor blockers have been administered to heavy alcohol drinking individuals. Therefore, we evaluated the safety, tolerability, pharmacokinetic (PK), pharmacodynamic (PD) and behavioral effects of a novel ghrelin receptor inverse agonist, PF-5190457, when co-administered with alcohol. We tested the effects of PF-5190457 combined with alcohol on locomotor activity, loss-of-righting reflex (a measure of alcohol sedative actions), and on blood PF-5190457 concentrations in rats. Then, we performed a single-blind, placebo-controlled, within-subject human study with PF-5190457 (placebo/0 mg b.i.d., 50 mg b.i.d., 100 mg b.i.d.). Twelve heavy drinkers during three identical visits completed an alcohol administration session, subjective assessments, and an alcohol cue-reactivity procedure, and gave blood samples for PK/PD testing. In rats, PF-5190457 did not interact with the effects of alcohol on locomotor activity or loss-of-righting reflex. Alcohol did not affect blood PF-5190457 concentrations. In humans, all adverse events were mild or moderate and did not require discontinuation or dose reductions. Drug dose did not alter alcohol concentration or elimination, alcohol-induced stimulation or sedation, or mood during alcohol administration. Potential PD markers of PF-5190457 were acyl-to-total ghrelin ratio and insulin-like growth factor-1. PF-5190457 (100 mg b.i.d.) reduced alcohol craving during the cue-reactivity procedure. This study provides the first translational evidence of safety and tolerability of the ghrelin receptor inverse agonist PF-5190457 when co-administered with alcohol. PK/PD/behavioral findings support continued research of PF-5190457 as a potential pharmacological agent to treat alcohol use disorder.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}