Clinical Psychoneuroendocrinology and Neuropsychopharmacology (CPN)

National Institute On Drug Abuse

Investigators

Linked publications, trials & patents

Abstract

The joint NIDA-NIAAA CPN Section conducts translational and clinical studies to identify possible novel medications for addiction. We are particularly interested in understanding the role of the gut-liver-brain axis and other peripheral-central mechanisms underlying alcohol use and their potential role as novel pharmacotherapeutic targets. This report summarizes work conducted in the CPN section, including collaborative efforts with many other scientists in the NIDA IRP, other NIH Institutes, as well as with academic centers. The ghrelin system might represent a novel pharmacological target for AUD treatment. To test whether GHS-R1a blockade may represent a pharmacotherapy for AUD, we developed a translational project to assess the effect of a GHS-R1a blocker, PF-5190457. In addition to safety assessments and pharmacokinetic characterization in rodents, we conducted a Phase 1b clinical study and showed that PF-5190457, co-administered with alcohol, is safe, tolerable and does not affect alcohol pharmacokinetics (Lee et al., Mol Psychiatry 2020). We also completed a Phase 2a clinical study to assess the efficacy of this compound in reducing alcohol craving and its potential effects on food craving/choices in patients with AUD (data analysis ongoing). By using a reverse translational bed-to-bench approach, we discovered a major metabolite of PF-5190457, named PF-6870961 (Adusumalli et al., Drug Metab Dispos. 2019). We further evaluated potential off-target binding of PF-6870961 through a radioligand binding high-throughput screen; no off-target binding of PF-6870961 was shown for any of the 84 targets evaluated. We also found that PF-6870961 binds to GHS-R1a, albeit with weaker affinity than the parent compound. Dose-dependent inhibition of the GOAT enzyme was not observed for either PF-6870961 or PF-5190457. Finally, the inhibition potency of PF-6870961 and PF-5190457 were evaluated using inositol trisphosphate (IP3) and -arrestin mobilization assays. PF-5190457 and PF-6870961 inhibit IP3 mobilization, with higher EC50 values than LEAP-2 (a recently discovered endogenous ghrelin antagonist) for both constitutive GHS-R1a and ghrelin-activated receptor activity. For -arrestin assays, the opposite was observed, with PF-5190457 and PF-6870961 having lower EC50 values than LEAP-2, suggesting improved activity through this signaling pathway (Deschaine et al., under review). As a way of targeting the ghrelin system with a different approach, we also started another clinical protocol to test the safety and efficacy of a GOAT inhibitor in non-treatment-seeking individuals with (recruitment ongoing). Beyond alcohol, we recently showed that acquisition of either cocaine or oxycodone self-administration in rats is associated with increased peripheral ghrelin levels and with upregulated GHS-R1a mRNA levels in dopamine neurons in the VTA. Additionally, systemic injections of the GHS-R1a antagonist JMV2959 decreased both cocaine and oxycodone self-administration in wild-type, but not GHS-R1a knock-out, rats. We also found that JMV2959 injection decreases cue-induced reinstatement of oxycodone and cocaine seeking, and brain stimulation reward, maintained by optogenetic stimulation of VTA dopamine neurons, or enhancement of this effect by cocaine (You et al., Neuropsychopharmacology 2021; Mol Psychiatry 2022). We are also investigating other gut-brain and peripheral-central neuroendocrine pathways in relation to alcohol use and addictive behaviors. Following on our early work (Suchankova et al., Transl Psychiatry 2015), we conducted an imaging-genetics study and found that genetic variation at the GLP-1R, i.e., two missense SNPs that result in amino-acid substitutions and putative changes in the GLP-1R were differentially associated with within-network brain functional connectivity among individuals with high versus low severity of alcohol use (Farokhnia, Fede et al., Sci Rep 2022). We also performed a series of secondary analyses and found that alcohol intake, with different doses and routes of administration (oral and IV) reduced peripheral GLP-1 levels in heavy-drinking individuals with AUD. In a human postmortem brain study, fold change of GLP-1R mRNA in hippocampus was significantly higher in individuals with AUD, compared to controls, and a less robust effect, but in the same direction, was found in PFC (Farokhnia et al., Addict Biol 2022). These data, along with previous rodent work, suggest that targeting the GLP-1 system may represent a novel pharmacotherapy for AUD. Following our previous work testing long-acting GLP-1 analogues in animal models of alcohol use (Marty, Farokhnia, et al., Front Neurosci 2020), we conducted a set of experiments and found that semaglutide dose-dependently decreased alcohol binge drinking (drinking-in-the dark) in mice and reduced operant alcohol self-administration in both alcohol-dependent and non-dependent rats. In collaboration with Scripps Research Institute, we have also conducted electrophysiology work to shed light on the effects semaglutide on GABA transmission in the central amygdala and infralimbic cortex of nave and alcohol-dependent rodents (Chuong, Farokhnia, Khom, et al., in preparation). Following up on our early translational work showing that the aldosterone/mineralocorticoid system is involved in alcohol seeking and related outcomes (Aoun et al., Mol Psychiatry 2018), we have started to investigate this neuroendocrine system as a potential pharmacotherapeutic target for AUD. In collaboration with Kaiser Permanente North California, we conducted a retrospective high-dimensional propensity score-matched cohort study showing that dispensation of the MR antagonist spironolactone was associated with significant reduction in weekly alcohol use, with a significant dose-response (Palzes et al., Neuropsychopharmacology 2021). In a series of rodent experiments, we demonstrated that spironolactone dose-dependently reduced the intake of sweetened or unsweetened alcohol solutions in mice (drinking-in-the-dark) and suppressed operant alcohol self-administration in dependent and nondependent rats (vapor exposure). In a second and much larger/longer pharmacoepidemiologic cohort study, we found a greater reduction in AUDIT-C scores among those who received spironolactone (for at least 60 days), compared to propensity-score matched controls. The largest effects were among those who reported hazardous alcohol consumption at baseline (AUDIT-C 8) and those exposed to 50 mg/day of spironolactone (Farokhnia, Rentsch, Chuong, McGinn et al., Mol Psychiatry 2022). We have also continued our work on non-pharmacological elements of the gut-brain axis in relation to alcohol use, including a recently completed clinical protocol (17-AA-0093) on gut microbiome in AUD (data analysis ongoing) and a nationwide survey study aimed at understanding the role and correlates of bariatric surgery in relation to AUD and other addictive behaviors (data collection ongoing).