| 1. |
- Addolorato, Giovanni, et al.
(författare)
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Hormones and drinking behaviour: new findings on ghrelin, insulin, leptin and volume-regulating hormones. An ESBRA Symposium report.
- 2009
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Ingår i: Drug and alcohol review. - : Wiley. - 1465-3362 .- 0959-5236. ; 28:2, s. 160-5
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Tidskriftsartikel (refereegranskat)abstract
- There is growing evidence for a role of appetite-related peptides and volume-regulating hormones in alcoholism. In particular, recent evidence has suggested that hormones, such as ghrelin, insulin and leptin and volume-regulating hormones, could play a role in alcohol-seeking behaviour. The goal of this review is to discuss the results of recent preclinical and clinical investigations on this topic. The findings indicate that neuroendocrinological mechanisms are potentially involved in the neurobiology of alcohol craving. Accordingly, research on this topic could lead to possible development of new therapeutic approaches in the treatment of patients with alcohol problems.
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| 2. |
- Heilig, Markus, et al.
(författare)
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Addiction as a brain disease revised : why it still matters, and the need for consilience
- 2021
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Ingår i: Neuropsychopharmacology. - : Springer Nature. - 0893-133X .- 1740-634X. ; 46:10, s. 1715-1723
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Forskningsöversikt (refereegranskat)abstract
- The view that substance addiction is a brain disease, although widely accepted in the neuroscience community, has become subject to acerbic criticism in recent years. These criticisms state that the brain disease view is deterministic, fails to account for heterogeneity in remission and recovery, places too much emphasis on a compulsive dimension of addiction, and that a specific neural signature of addiction has not been identified. We acknowledge that some of these criticisms have merit, but assert that the foundational premise that addiction has a neurobiological basis is fundamentally sound. We also emphasize that denying that addiction is a brain disease is a harmful standpoint since it contributes to reducing access to healthcare and treatment, the consequences of which are catastrophic. Here, we therefore address these criticisms, and in doing so provide a contemporary update of the brain disease view of addiction. We provide arguments to support this view, discuss why apparently spontaneous remission does not negate it, and how seemingly compulsive behaviors can co-exist with the sensitivity to alternative reinforcement in addiction. Most importantly, we argue that the brain is the biological substrate from which both addiction and the capacity for behavior change arise, arguing for an intensified neuroscientific study of recovery. More broadly, we propose that these disagreements reveal the need for multidisciplinary research that integrates neuroscientific, behavioral, clinical, and sociocultural perspectives.
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| 3. |
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| 4. |
- Lee, Mary R., et al.
(författare)
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The novel ghrelin receptor inverse agonist PF-5190457 administered with alcohol: preclinical safety experiments and a phase 1b human laboratory study
- 2020
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Ingår i: Molecular Psychiatry. - : NATURE PUBLISHING GROUP. - 1359-4184 .- 1476-5578. ; 25:2, s. 461-475
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Tidskriftsartikel (refereegranskat)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.
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| 5. |
- MacKillop, James, et al.
(författare)
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Hazardous drinking and alcohol use disorders
- 2022
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Ingår i: NATURE REVIEWS DISEASE PRIMERS. - : NATURE PORTFOLIO. - 2056-676X. ; 8:1
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Tidskriftsartikel (refereegranskat)abstract
- Alcohol is one of the most widely consumed psychoactive drugs globally. Hazardous drinking, defined by quantity and frequency of consumption, is associated with acute and chronic morbidity. Alcohol use disorders (AUDs) are psychiatric syndromes characterized by impaired control over drinking and other symptoms. Contemporary aetiological perspectives on AUDs apply a biopsychosocial framework that emphasizes the interplay of genetics, neurobiology, psychology, and an individuals social and societal context. There is strong evidence that AUDs are genetically influenced, but with a complex polygenic architecture. Likewise, there is robust evidence for environmental influences, such as adverse childhood exposures and maladaptive developmental trajectories. Well-established biological and psychological determinants of AUDs include neuroadaptive changes following persistent use, differences in brain structure and function, and motivational determinants including overvaluation of alcohol reinforcement, acute effects of environmental triggers and stress, elevations in multiple facets of impulsivity, and lack of alternative reinforcers. Social factors include bidirectional roles of social networks and sociocultural influences, such as public health control strategies and social determinants of health. An array of evidence-based approaches for reducing alcohol harms are available, including screening, pharmacotherapies, psychological interventions and policy strategies, but are substantially underused. Priorities for the field include translating advances in basic biobehavioural research into novel clinical applications and, in turn, promoting widespread implementation of evidence-based clinical approaches in practice and health-care systems.
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| 6. |
- Pietrzak, Michal, et al.
(författare)
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A randomized controlled experimental medicine study of ghrelin in value-based decision making
- 2023
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Ingår i: Journal of Clinical Investigation. - : AMER SOC CLINICAL INVESTIGATION INC. - 0021-9738 .- 1558-8238. ; 133:12
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND. The stomach-derived hormone ghrelin stimulates appetite, but the ghrelin receptor is also expressed in brain circuits involved in motivation and reward. We examined ghrelin effects on decision making beyond food or drug reward using monetary rewards. METHODS. Thirty participants (50% women and 50% men) underwent 2 fMRI scans while receiving i.v. ghrelin or saline in a randomized counterbalanced order. RESULTS. Striatal representations of reward anticipation were unaffected by ghrelin, while activity during anticipation of losses was attenuated. Temporal discounting rates of monetary reward were lower overall in the ghrelin condition, an effect driven by women. Discounting rates were inversely correlated with neural activity in a large cluster within the left parietal lobule that included the angular gyrus. Activity in an overlapping cluster was related to behavioral choices and was suppressed by ghrelin. CONCLUSION. This is, to our knowledge, the first human study to extend the understanding of ghrelins significance beyond the canonical feeding domain or in relation to addictive substances. Contrary to our hypothesis, we found that ghrelin did not affect sensitivity to monetary reward anticipation, but rather resulted in attenuated loss aversion and lower discounting rates for these rewards. Ghrelin may cause a motivational shift toward caloric reward rather than globally promoting the value of reward. TRIAL REGISTRATION. EudraCT 2018-004829-82.
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| 7. |
- Pietrzak, Michal, 1987-, et al.
(författare)
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Ghrelin decreases sensitivity to negative feedback and increases prediction-error related caudate activity in humans, a randomized controlled trial
- 2024
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Ingår i: Neuropsychopharmacology. - : Springer Science+Business Media B.V.. - 0893-133X .- 1740-634X. ; 49, s. 1042-1049
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Tidskriftsartikel (refereegranskat)abstract
- The stomach-derived hormone ghrelin plays not only a role in feeding, starvation, and survival, but it has been suggested to also be involved in the stress response, in neuropsychiatric conditions, and in alcohol and drug use disorders. Mechanisms related to reward processing might mediate ghrelin's broader effects on complex behaviors, as indicated by animal studies and mostly correlative human studies. Here, using a within-subject double-blind placebo-controlled design with intravenous ghrelin infusion in healthy volunteers (n = 30), we tested whether ghrelin alters sensitivity to reward and punishment in a reward learning task. Parameters were derived from a computational model of participants' task behavior. The reversal learning task with monetary rewards was performed during functional brain imaging to investigate ghrelin effects on brain signals related to reward prediction errors. Compared to placebo, ghrelin decreased punishment sensitivity (t = -2.448, p = 0.021), while reward sensitivity was unaltered (t = 0.8, p = 0.43). We furthermore found increased prediction-error related activity in the dorsal striatum during ghrelin administration (region of interest analysis: t-values >= 4.21, p-values <= 0.044). Our results support a role for ghrelin in reward processing that extends beyond food-related rewards. Reduced sensitivity to negative outcomes and increased processing of prediction errors may be beneficial for food foraging when hungry but could also relate to increased risk taking and impulsivity in the broader context of addictive behaviors.
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| 8. |
- Proto, Monica, et al.
(författare)
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Transport Infrastructure Surveillance and Monitoring by Electromagnetic Sensing : The ISTIMES Project
- 2010
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Ingår i: Sensors. - : MDPI AG. - 1424-8220. ; 10:12, s. 10620-10639
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Tidskriftsartikel (refereegranskat)abstract
- The ISTIMES project, funded by the European Commission in the frame of a joint Call "ICT and Security" of the Seventh Framework Programme, is presented and preliminary research results are discussed. The main objective of the ISTIMES project is to design, assess and promote an Information and Communication Technologies (ICT)-based system, exploiting distributed and local sensors, for non-destructive electromagnetic monitoring of critical transport infrastructures. The integration of electromagnetic technologies with new ICT information and telecommunications systems enables remotely controlled monitoring and surveillance and real time data imaging of the critical transport infrastructures. The project exploits different non-invasive imaging technologies based on electromagnetic sensing (optic fiber sensors, Synthetic Aperture Radar satellite platform based, hyperspectral spectroscopy, Infrared thermography, Ground Penetrating Radar-, low-frequency geophysical techniques, Ground based systems for displacement monitoring). In this paper, we show the preliminary results arising from the GPR and infrared thermographic measurements carried out on the Musmeci bridge in Potenza, located in a highly seismic area of the Apennine chain (Southern Italy) and representing one of the test beds of the project.
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| 9. |
- Ray, Lara A., et al.
(författare)
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The future of translational research on alcohol use disorder
- 2021
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Ingår i: Addiction Biology. - : WILEY. - 1355-6215 .- 1369-1600. ; 26:2
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Forskningsöversikt (refereegranskat)abstract
- In March 2019, a scientific meeting was held at the University of California, Los Angeles (UCLA) Luskin Center to discuss approaches to expedite the translation of neurobiological insights to advances in the treatment of alcohol use disorder (AUD). A guiding theme that emerged was that while translational research in AUD is clearly a challenge, it is also a field ripe with opportunities. Herein, we seek to summarize and disseminate the recommendations for the future of translational AUD research using four sections. First, we briefly review the current landscape of AUD treatment including the available evidence-based treatments and their uptake in clinical settings. Second, we discuss AUD treatment development efforts from a translational science viewpoint. We review current hurdles to treatment development as well as opportunities for mechanism-informed treatment. Third, we consider models of translational science and public health impact. Together, these critical insights serve as the bases for a series of recommendations and future directions. Towards the goal of improving clinical care and population health for AUD, scientists are tasked with bolstering the clinical applicability of their research findings so as to expedite the translation of knowledge into patient care.
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| 10. |
- Schwandt, Melanie L., et al.
(författare)
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The CRFI Antagonist Verucerfont in Anxious Alcohol-Dependent Women: Translation of Neuroendocrine, But not of Anti-Craving Effects
- 2016
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Ingår i: Neuropsychopharmacology. - : Nature Publishing Group. - 0893-133X .- 1740-634X. ; 41:12, s. 2818-2829
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Tidskriftsartikel (refereegranskat)abstract
- Blockade of corticotropin-releasing factor receptor I (CRFI) suppresses stress-induced alcohol seeking in rodents, but clinical translation remains. Here, we first showed that the CRFI antagonist verucerfont potently blocks hypothalamic-pituitary adrenal (HPA) axis activation in adrenalectomized rats. We then evaluated verucerfont for its ability to block HPA axis activation and reduce stress-induced alcohol craving in alcohol-dependent patients. Anxious, alcohol-dependent women (age 21-65 years, n = 39) were admitted to the NIH Clinical Center and completed withdrawal treatment before enrollment if needed. One-week single-blind placebo was followed by randomized double-blind verucerfont (350 mg per day) or placebo for 3 weeks. Verucerfont effects on the HPA axis were evaluated using the dexamethasone-CRF test Craving was evaluated using two established protocols, one that combines a social stressor with physical alcohol cue exposure, and one that uses guided imagery to present personalized stress, alcohol, or neutral stimuli. An fMRI session examined brain responses to negative affective stimuli and alcohol cues. In contrast to our recent observations with another CRFI antagonist, pexacerfont, verucerfont potently blocked the HPA axis response to the dexamethasone-CRF test, but left alcohol craving unaffected. Right amygdala responses to negative affective stimuli were significantly attenuated by verucerfont, but responses to alcohol-associated stimuli were increased in some brain regions, including left insula. Discontinuation rates were significantly higher in the verucerfont group. Our findings provide the first translational evidence that CRFI antagonists with slow receptor dissociation kinetics may have increased efficacy to dampen HPA axis responses. The findings do not support a clinical efficacy of CRFI blockade in stress-induced alcohol craving and relapse.
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