Effects of 5-HT2C, 5-HT1A receptor challenges and modafinil on the initiation and persistence of gambling behaviours

Abstract

Rationale Problematic patterns of gambling are characterised by loss of control and persistent gambling often to recover losses. However, little is known about the mechanisms that mediate initial choices to begin gambling and then continue to gamble in the face of losing outcomes. Objectives These experiments first assessed gambling and loss-chasing performance under different win/lose probabilities in C57Bl/6 mice, and then investigated the effects of antagonism of 5-HT 2C R with SB242084, 5-HT 1A R agonism with 8-OH-DPAT and modafinil, a putative cognitive enhancer. Results As seen in humans and other species, mice demonstrated the expected patterns of behaviour as the odds for winning were altered increasing gambling and loss-chasing when winning was more likely. SB242084 decreased the likelihood to initially gamble, but had no effects on subsequent gambling choices in the face of repeated losses. In contrast, 8-OH-DPAT had no effects on choosing to gamble in the first place, but once started 8-OH-DPAT increased gambling choices in a dose-sensitive manner. Modafinil effects were different to the serotonergic drugs in both decreasing the propensity to initiate gambling and chase losses. Conclusions We present evidence for dissociable effects of systemic drug administration on different aspects of gambling behaviour. These data extend and reinforce the importance of serotonergic mechanisms in mediating discrete components of gambling behaviour. They further demonstrate the ability of modafinil to reduce gambling behaviour. Our work using a novel mouse paradigm may be of utility in modelling the complex psychological and neurobiological underpinnings of gambling problems, including the analysis of genetic and environmental factors.

Exploring the underlying mechanisms of drug‐induced impulse control disorders: a pharmacovigilance‐pharmacodynamic study

“…Within the two populations (i.e. dopamine agonist reports and antipsychotic reports, see Supplementary Material-Table S2 and S3), ICD reports were characterized by a significantly higher proportion of men (50.58% vs 47.56% in antipsychotics; 59.90% vs 39.46% in dopamine agonists) and younger age (median[Q1-Q3] = 42 years vs 50 in antipsychotics; 56 [48][49][50][51][52][53][54][55][56][57][58][59][60][61][62][63][64][65] vs 66 in dopamine agonists). Lower proportions of deaths (2.05% vs 12.20% in antipsychotics; 2.42% vs 7.62% in dopamine agonists) and higher of disability (9.60% vs 1.95%; 4.42% vs 2.26%) were also reported.…”

“…The onset of ICDs was earlier for antipsychotics (median [Q1-Q3] = 31 [1-366] days, on 1871 available time to onset data) than for dopamine agonists (214 days, on 662 available time to onset data). Dopamine-agonist related ICDs, compared to antipsychotic-related ICDs, also had higher contribution by men (59.90% vs 50.58%) and older people (56 [48][49][50][51][52][53][54][55][56][57][58][59][60][61][62][63][64][65] vs 42 years old). Finally, the 254 ICD cases recording the use of both dopamine agonists and antipsychotics (Table S4) shared the characteristics of ICDs occurring with dopamine agonists (men 60.00%, age 56 ), but were more similar to ICDs occurring with antipsychotics in the lawyer contribution (15.29%) and the reported disability rate (8.27%), and the reported hospitalization rate (42.13%) was substantially higher than when developing ICDs with dopamine agonists (16.84%) or antipsychotics (32.50%).…”

“…Therefore, it may potentially contribute to the development of ICDs by inhibiting the serotonergic pathway usually involved in impulse control, resulting in an increased motivational drive. Indeed, its agonism, particularly at low doses, was observed to induce-reward-driven behaviors 57 ; 5-HT1a-receptor agonism has been found to induce impulsivity in mice 58,59 and rats [60][61][62] ; 5-HT1a-receptor antagonism reduces impulsivity in rats 63 ; 5-HT1A gene polymorphisms bring susceptibility in humans. 64,65 Therefore, we believe that our hypothesis including 5-HT1areceptor agonism as one of the main pathogenetic mechanisms of iatrogenic ICDs is promising and deserves to be further investigated.…”

Impulse Control Disorders by Dopamine Partial Agonists: A Pharmacovigilance-Pharmacodynamic Assessment Through the FDA Adverse Event Reporting System

“…This is coherent with the finding, in Parkinson’s disease, that ICDs are associated with an increased release of dopamine in the ventral striatum ( Martini et al, 2018 ), which opposes the prevailing hypothesis of a primary role related to the exogenous dopaminergic activity. Interestingly, different studies have already demonstrated 5-HT1A–induced impulsivity and addiction in mice ( Humby et al, 2020 ; Chu et al, 2021 ) and investigated the relationship between impulsivity and 5-HT1A polymorphisms in humans ( Benko et al, 2010 ; Stamatis et al, 2020 ). Furthermore, 5-HT1A agonists such as buspirone and vortioxetine may cause impulsive-compulsive behaviors in rats ( Liu et al, 2004 ; Lu et al, 2013 ; Martis et al, 2021 ), and a 5-HT1A partial agonist (tandospirone) may result in reduced impulsivity in rats because of its 5-HT1A antagonistic activity ( Ohmura et al, 2013 ).…”

Behavioural expressions of loss-chasing in gambling: A systematic scoping review

“…In addition, it will be fruitful to explore novel paradigms that can capture key cognitive processes that may be involved in between-session and within-session loss-chasing. For instance, recent work developed a new behavioural task that allowed rats to initiate gambling (which might be related to between-session loss-chasing) or continue gambling after starting (which might be related to within-session loss-chasing), and showed that these two decisions have dissociable neurochemical underpinnings (Humby et al, 2020). An interesting avenue for future research can be to examine whether the decisions to initiate or continue gambling in such tasks can be related to loss-chasing between-and within-session among gamblers.…”