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Background and Aims: Gambling Disorder (GD) is considered a heterogeneous, multidimensional pathology with high personal and social consequences. The transition time (TT) between problematic gaming and pathological gambling, which varies significantly across patients, may predict the disorder's severity. As only limited studies have investigated the factors implicated in the TT, the current study set out to identify its predictors and their relationships with GD severity., Methods: Correlation were performed in 725 male GD patients to identify factors associated to TT and GD severity, including: age of onset of gambling behaviors, alcohol/drug use, personality traits and gambling preferences (i.e., strategic, non-strategic, and mixed). Then a regression analysis was performed to identify predictors of TT to GD., Results: Longer TT correlated with higher GD severity, early age of onset of problematic gambling, substance use and a non-strategic gambling preference. Personality traits including low self-directedness, high novelty seeking, and low cooperativeness were also related with longer TT. The strongest associations with GD severity were substance use, and some of the personality traits (i.e., low self-directedness and cooperativeness, high harm avoidance and self-transcendence). Factors significantly predicting longer transition to GD were older ages, low self-directedness, and non-strategic gambling., Conclusions: A clinical profile characterized by a longer TT and more severe GD symptoms pertains to older patients with low self-directedness, and preference for non-strategic gambling. Other relevant factors associated with this profile of patients included early age of onset problematic gambling, substance consumption, high novelty seeking and low cooperativeness., (Copyright © 2021 Elsevier Ltd. All rights reserved.)

Introduction: Despite intense neuroscience research on the neurobiological underpinnings of Gambling Disorder (GD) and gambling-related decision-making, effective treatments targeting these dysfunctions are still lacking. Non Invasive Brain Stimulation (NIBS) techniques, such as transcranial Direct Current Stimulation (tDCS) and Transcranial Magnetic Stimulation (TMS), selectively modulate activity of brain circuits and have the potential to reverse alterations sustaining GD symptoms. Therefore, the aim of this systematic review was to determine the impact of different NIBS interventions on gambling-related decision processes., Methods: We conducted a comprehensive and translational search in three online databases (MEDLINE via PubMed, Scopus, Web of Science), in accordance with the PRISMA guidelines. We included studies applying neuromodulation (TMS, tDCS) techniques in GD patients or assessing gambling-related decision-making in healthy subjects. In addition, we explored the potential impact of NIBS in drug-induced GD (e.g., Parkinson's Disease)., Results: Twenty-seven studies have been included. We summarized results to detect the impact of different targets and stimulation/inhibition protocols in terms of gambling-related decision-making. The majority of both tDCS and TMS studies targeted the dorsolateral prefrontal cortex. Although heterogeneous in protocols and parameters, results from tDCS and TMS studies converge in indicating that the stimulation (instead of inhibition) of prefrontal regions could be beneficial to contrast dysfunctional gambling-related decision processes., Conclusion: NIBS interventions show promise to be further tested in controlled clinical settings for the treatment of behavioral addictions. Further studies are also necessary to investigate connectivity changes and laterality issues (unilateral versus bilateral; left versus right) of NIBS application in GD., (Copyright © 2020 Elsevier Ltd. All rights reserved.)

Dopamine has a crucial and well-documented role in the development and maintenance of Gambling Disorder (GD). This systematic review adopts a translational approach aimed at providing a comprehensive synthesis of current clinical and preclinical knowledge on dopaminergic function in GD at a neurobiological level. To this end, we present and discuss converging dopaminergic alterations and phenotypes. Preclinical and clinical review protocols were registered on the PROSPERO database (CRD42019124404, CRD42019124405). The literature search was conducted in accordance with PRISMA guidelines using three databases (PubMed, Web of Science, Scopus). We identified 67 preclinical studies using pharmacological and non-pharmacological manipulations of the gambling-like phenotype and 33 human studies investigating either genetic polymorphisms or functional brain imaging data. Dopamine transporter and D2, D3, D4 receptor alterations showed strongest translational concordance. Though no postsynaptic dopaminergic alterations were observed, several studies point at dysfunctions in presynaptic dopamine trafficking in GD, suggestive of hyperdopaminergic states. Developing meaningful translational models is essential to working towards the development of an integrated conceptual framework for GD and neurobiologically-based treatment interventions., (Copyright © 2020 Elsevier Ltd. All rights reserved.)

The Naples High-Excitability (NHE) is a validated rat strain to model for a mesocortical variant of Attention Deficit Hyperactivity Disorder (ADHD). NHE rats' brains have a tuned-down cortical and a potentiated limbic loop (Zoratto et al., 2017). ADHD and comorbid pathological gambling (PG) involve similar deficits of prefrontal-striatal dialogue. This work aimed to understand if NHE rats (compared to normal random-bred rats, NRB) can be a useful model for gambling vulnerability in ADHD. Experiment 1 evaluated gambling proneness in NHE rats, namely attraction/avoidance in nose-poking for a "Large & Luck-Linked" (LLL) reward (versus a "Small & Sure" one, SS), when the probability of LLL delivery was progressively reduced. Experiment 2 assessed (by phMRI) differential responsivity of ventral (vStr) versus dorsal (dStr) striatum following a methylphenidate (MPH, 4 mg/kg I.P.) challenge. In NHE rats, reduced attraction by secondary cues (associated with uncertain, rarefying LLL delivery) comes along with little or no activation of dStr and enhanced activation of vStr by MPH. Together, such evidences from NHE rats indicate distinctive roles of ventral (enhanced value given to actual primary reward) and dorsal (lower encoding of repeated stimulus-reward associations into a habit) striatum. In conclusion, the dynamics of reward systems could link an attention deficit with a decreased vulnerability to pathological gambling., Competing Interests: Declaration of Competing Interest None., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Gambling disorder (GD) is a topical problem in developed countries and may be present in 1-3% of the general population. The pathophysiology of this disorder is largely unknown but it shares similarities to other behavioral addictions. Multiple neurotransmitter systems, including dopaminergic, serotonergic, noradrenergic, glutamatergic, and opioidergic, have been implicated in GD. Based on available articles, only the opioid antagonist naltrexone has been documented to demonstrate clinical efficacy in multiple studies including double-blind studies. Nalmefene, another opioid antagonist, may be active as well but its dose-response effect remains unclear. Contrarily, current test results do not support the therapeutic use of any antidepressant drug. Some positive data has been made available supporting the use of N-acetylcystein, but more studies are needed to confirm this. No clear or definite information is currently available for other drugs., (© 2017 Wiley Periodicals, Inc.)

Gambling Disorder (GD) is characterized by excessive gambling despite adverse consequences on individual functioning. In spite of some positive findings, it is difficult to draw any conclusion on the genetics of GD. Indeed, beyond DNA sequence variation, other regulatory mechanisms (like those that engage epigenetics) may explain gene alterations in this addictive disease. Wistar male rats underwent an operant task for the evaluation of individual propensity to gamble. Few rats, after having learnt to prefer nose-poking for a large over a small food reward, were sacrificed to obtain a baseline profile of gene expression at both central and peripheral levels. In the remaining rats, probability of occurrence of large-reward delivery decreased progressively to very low levels. Thus, rats were faced with temptation to "gamble", i.e. to nose-poke for a binge reward, whose delivery was omitted the majority of times. After 3weeks of testing, rats showing a clear-cut profile of either gambling proneness or aversion were selected and sacrificed after the last session. A selective down-regulation of i) serotonin transporter in prefrontal cortex, ii) tyrosine hydroxylase in ventral striatum, iii) dopamine transporter in lymphocytes was evidenced in "gambler" vs "non-gambler" rats. The exposure to such operant task (compared to home-cage alone) modulated ventrostriatal but not prefrontal genes. A consistent increase of DNA methylation, in one specific CpG site at serotonin transporter gene, was evident in prefrontal cortex of "gambler" rats. Elucidation of epigenetic changes occurring during GD progression may pave the way to the development of new therapeutic strategies through specific modulation of epigenetic factors., (Copyright © 2016 IBRO. Published by Elsevier Ltd. All rights reserved.)

Interest is rising for animal modeling of pathological gambling. Using the operant probabilistic-delivery task (PDT), gambling proneness can be evaluated in laboratory animals. Drawing a comparison with rats, this study evaluated the common marmoset (Callithrix jacchus) using a PDT. By nose- or hand-poking, subjects learnt to prefer a large (LLL, 5-6 pellets) over a small (SS, 1-2 pellets) reward and, subsequently, the probability of occurrence of large-reward delivery was decreased progressively to very low levels (from 100% to 17% and 14%). As probability decreased, subjects showed a great versus little shift in preference from LLL to SS reinforcer. Hence, two distinct subpopulations ("non-gambler" versus "gambler") were differentiated within each species. A proof of the model validity comes from marmosets' reaction to reward-delivery omission. Namely, depending on individual temperament ("gambler" versus "non-gambler"), they showed either persistence (i.e., inadequate pokes towards LLL) or restlessness (i.e., inadequate pokes towards SS), respectively. In conclusion, the marmoset could be a suitable model for preclinical gambling studies. Implementation of the PDT to species other than rats may be relevant for determining its external validity/generalizability and improving its face/construct validity.

Pathological gambling is widespread among adolescents (3-8%). Gambling proneness can be evaluated in animals using the Probabilistic Delivery (PD) task. In this operant protocol, rats learn to choose for large over small reward. Subsequently, the probability of large reward-delivery decreases progressively to very low levels. Using a home-cage version of the PD task, we studied (Exp. 1-3) the development of preference for the largest reward in middle (pnd 34-35) and late (pnd 48-49) adolescent rats, using the standard paradigm (Zoratto et al., 2012) and then modifying: (i) probability "p" initially associated with the largest reward; (ii) size difference between rewards; (iii) "removable" or "fixed" partitions (allowing to house animals in couples, separating them only during testing). The standard paradigm (p = 50%, 2 vs 6 pellets; "removable" partitions) does not allow the establishment of preference for the largest reward, at neither adolescent age. Conversely, the modified paradigm (p = 66%; 1 vs 5 pellets; "fixed" partitions) allows the development of such preference, already at pnd 34-35. By using the best combination of these factors, we then investigated (Exp. 4) the characteristics of gambling behaviour in middle adolescent (pnd 36-49) and young adult (pnd 67-80) rats. Gambling proneness appears slightly increased during adolescence when compared to adulthood. Notably, inadequate responses (expressed during post-choice timeout, 30 s) appear markedly reduced, suggesting developing animals to be insensitive to reward-delivery omission. In conclusion, methodological refinement is essential to allow the study of risk-prone behaviour during rat adolescence, thus contributing to a better understanding of psychobiological determinants of gambling., (Copyright © 2012 Elsevier Ltd. All rights reserved.)

Psycho-genetic studies have revealed a role for the brain serotonin system in gambling proneness and poor decision-making. We assessed whether manipulation of brain serotonin levels in rats affected performance in operant-based tasks for decision-making and gambling proneness. Male Wistar rats were exposed to an l-tryptophan (TRP) deficient diet (0.0 g/kg; T- group) or to a control, l-tryptophan containing diet (2.8 g/kg; T+ group). The same rats were tested for decision-making performance in the rodent Iowa Gambling Task (rIGT) using home-cage operant panels, and subsequently for gambling proneness in a Probabilistic Delivery Task (rPDT) using classic Skinnerboxes. At sacrifice, monoamines and metabolites were evaluated with HPLC analysis, confirming a drastically reduced serotonin synthesis, as well as altered dopamine turnover in the prefrontal cortex of T- rats. As expected, control rats (T+) progressively chose the option with the best long-term payoff in the rIGT, and also shifted from "Large & Luck-Linked" (LLL) to "Small & Sure" (SS) reinforcers in the rPDT. In contrast, depleted animals (T-) exhibited a weaker improvement of performance in the rIGT and maintained a sub-optimal attraction for LLL reinforcer in the rPDT. Comparing individual performances in both tests, we found a significant correlation between the two tasks in control (T+) but not in depleted (T-) rats. The present study revealed that (1) brain 5-HT depletion leads to poor decision-making and to gambling proneness; (2) the relationship between these two traits, shown in the control group, was disrupted in 5-HT depleted rats. The data are discussed in terms of changes within forebrain loops involved in cognitive and motivational/affective processes., (Copyright © 2011 Elsevier Ltd. All rights reserved.)