Daniela S. S. Lobo

The D2/3 dopamine receptor in pathological gambling: a positron emission tomography study with [11C]‐(+)‐propyl‐hexahydro‐naphtho‐oxazin and [11C]raclopride

AIMS Pathological gambling (PG) shares diagnostic features with substance use disorder (SUD), but the neurochemical mechanisms underlying PG are poorly understood. Because dopamine (DA), a neurotransmitter implicated in reward and reinforcement, is probably involved, we used positron emission tomography (PET) to test whether PG is associated with abnormalities in D2 and D3 receptor levels, as observed in SUD. DESIGN Case-control study comparing PG to healthy control (HC) subjects. SETTING Academic research imaging centre. PARTICIPANTS Thirteen non-treatment-seeking males meeting DSM-IV criteria for PG, and 12 matched HC (11 of whom completed PET). MEASUREMENTS Two PET scans (one with the D3 receptor preferring agonist [11C]-(+)-propyl-hexahydro-naphtho-oxazin (PHNO) and the other with [11C]raclopride) to assess D(2/3) DA receptor availability, and behavioural measures (self-report questionnaires and slot-machine game) to assess subjective effects and relationships to PET measures. FINDINGS Binding of both radiotracers did not differ between groups in striatum or substantia nigra (SN) (all P > 0.1). Across PG, [11C]-(+)-PHNO binding in SN, where the signal is attributable primarily to D3 receptors, correlated with gambling severity (r = 0.57, P = 0.04) and impulsiveness (r = 0.65, P = 0.03). In HC, [11C]raclopride binding in dorsal striatum correlated inversely with subjective effects of gambling (r = -0.70, P = 0.03) and impulsiveness (r = -0.70, P = 0.03). CONCLUSIONS Unlike with substance use disorder, there appear to be no marked differences in D2 /D3 levels between healthy subjects and pathological gamblers, suggesting that low receptor availability may not be a necessary feature of addiction. However, relationships between [11C]-(+)-PHNO binding and gambling severity/impulsiveness suggests involvement of the D3 receptor in impulsive/compulsive behaviours.

In vivo evidence for greater amphetamine-induced dopamine release in pathological gambling: a positron emission tomography study with [ 11 C]-(+)-PHNO

Drug addiction has been associated with deficits in mesostriatal dopamine (DA) function, but whether this state extends to behavioral addictions such as pathological gambling (PG) is unclear. Here we used positron emission tomography and the D3 receptor-preferring radioligand [11C]-(+)-PHNO during a dual-scan protocol to investigate DA release in response to oral amphetamine in pathological gamblers (n=12) and healthy controls (n=11). In contrast with human neuroimaging findings in drug addiction, we report the first evidence that PG is associated with greater DA release in dorsal striatum (54–63% greater [11C]-(+)-PHNO displacement) than controls. Importantly, dopaminergic response to amphetamine in gamblers was positively predicted by D3 receptor levels (measured in substantia nigra), and related to gambling severity, allowing for construction of a mechanistic model that could help explain DA contributions to PG. Our results are consistent with a hyperdopaminergic state in PG, and support the hypothesis that dopaminergic sensitization involving D3-related mechanisms might contribute to the pathophysiology of behavioral addictions.

Association of functional variants in the dopamine D2-like receptors with risk for gambling behaviour in healthy Caucasian subjects.

Pathological gambling (PG) is an impulse control disorder with suggestive genetic vulnerability component. We evaluated the association of genetic variants in the dopaminergic receptor genes (DRD1-3s) with risk for gambling in healthy subjects using the Canadian Problem Gambling Index (CPGI). Healthy Caucasian subjects who had gambled at least once in their lifetime (n=242) were included in the analysis. Gender was not associated with the CPGI, while younger age was associated with higher CPGI scores. We have found that none of the single polymorphisms investigated on DRD1 and DRD3 were associated with CPGI scores in healthy subjects. However, we observed trends for association on the TaqIA/rs1800497 polymorphism (P=0.10) and the haplotype flanking DRD2 (G/C/A rs11604671/rs4938015/rs2303380; P=0.06). Both trends were associated with lower CPGI score. Our results provide further evidence for the role of dopamine D2-like receptor in addiction susceptibility.

The Genetics of Gambling and Behavioral Addictions

Behavioral addictions are considered as the repetitive occurrence of impulsive behaviors without consideration of their potential negative consequences. These addictions represent an increasing cost to society and are an important new field of research in psychiatric genetics. There has been a growing body of evidence on the familial aggregation and genetic influences on the development of behavioral addictions and mainly on pathological gambling. The aim of this article is to critically review findings of family and molecular genetic studies on behavioral addictions, focusing on pathological gambling and commenting on other disorders where appropriate. This review provides a comprehensive approach to genetic studies on behavioral addiction and points out the necessity of expanding the genetic research in this field. Future directions for genetic studies in this field are also discussed.

Genetic Underpinnings of Neuroticism: A Replication Study

Background: Neuroticism, as defined and measured by the NEO Personality Inventory (Neuroticism Extraversion and Openness Personality Inventory), is a core personality trait reflecting an individuals emotional reactivity. High neuroticism is thought to be an important vulnerability factor for various psychiatric disorders in the general population, including substance abuse, depression, anxiety, and psychosis. Recent findings support the hypothesis that genetic factors underlying the neuroticism trait could increase the susceptibility to psychiatric disorders. The current study aimed to replicate genetic associations with high neuroticism previously reported in the literature. Methods: We genotyped four polymorphisms: CNR1 (rs7766029), GABRA2 (rs9291283), GABRA6 (rs3219151) and MAMDC1 (rs7151262) in 215 healthy Caucasian subjects, who completed a short version of the NEO-PI. NEO neuroticism scores of the three genotype groups were compared using ANCOVA, with age as a covariate. Results: All four genetic polymorphisms were found to be significantly associated with NEO neuroticism scores (p < 0.0025), but not with any other NEO personality domain. Conclusion: Our results corroborate other studies proposing a role for the GABAergic and cannabinoid systems in the modulation of affective states and stress responses, as measured through neuroticism scores. It is important to replicate the genetic findings of neuroticism, in order to gain a better understanding of this personality domain that has been reported as an important risk factor for mood and anxiety disorders and substance addiction.

Parallel role for the dopamine D1 receptor in gambling and amphetamine reinforcement in healthy volunteers

This study investigated the role of dopamine, and specifically the D1 receptor (D1R), in the reinforcing effects of a slot-machine game in healthy volunteers (n=30). To compare gambling and drug effects, subjects received the prototypic psychostimulant drug d-amphetamine (AMPH; 20 mg) in a multi-session, placebo-controlled design. To isolate D1R, half the subjects were pretreated with the preferential D2 receptor antagonist haloperidol (HAL; 3 mg), and the other half with the mixed D1–D2 antagonist fluphenazine (FLU; 3 mg) before the game (Phase I) and AMPH (Phase II). HAL decreased and FLU increased the post-game desire to gamble and post-AMPH desire to take AMPH again, as well as amphetamine scale ratings on the Addiction Research Center Inventory after gambling and AMPH. The effects of the antagonists on desire to gamble and to take AMPH again were significantly intercorrelated. HAL increased and FLU decreased the salience of negative affective words on a rapid reading task after both reinforcers. HAL also decreased the salience of gambling words after AMPH. Both reinforcers increased diastolic blood pressure equally under antagonists and placebo. Results indicate that D1R plays a parallel role in the psychostimulant-like, incentive-motivational, and salience-enhancing effects of gambling and AMPH. Moderate D1R activation appears to optimize these effects in healthy subjects.

Hitting the jackpot: the influence of monetary payout on gambling behaviour

Abstract Restrictions on monetary payout may promote player engagement in gambling as a form of entertainment rather than as a source of income. Our objective was to evaluate the effects of monetary prize magnitude upon gambling behaviour in a community sample, and the degree to which this association is moderated by gambling risk factors. One hundred and eighty-seven adults completed an online survey assessing motivation, impulsivity and affect. Participants were given a series of vignettes and asked to estimate how much they would gamble to win monetary prizes of increasing amounts with and without accrued gambling debt. Participants reported increased gambling in response to increased monetary payout. Debt moderated these outcomes, such that electronic gaming machine (EGM) and lottery expenditures and number of lottery games played decreased with increased debt; this effect was most pronounced at elevated monetary prizes. The association between duration of EGM play and monetary payout was moderated by gender only. Results suggest that self-reported gambling behaviours increased with monetary payout even across qualitatively different gambling products, and across gamblers with different motivations for gambling, levels of impulsivity, and negative affect. The restriction of monetary payouts warrants further research attention as a form of problem gambling prevention.

Differential cardiovascular and hypothalamic pituitary response to amphetamine in male pathological gamblers versus healthy controls

Cardiovascular and hypothalamic pituitary axis (HPA) disturbances have been observed in individuals who are pathological gamblers (PGs). These may partly derive from chronic exposure to gambling. Response to amphetamine (AMPH) may reveal such disturbances while controlling for differential conditioned responses to gambling in PGs vs healthy controls (HCs). This study assessed heart rate (HR), systolic blood pressure (SBP) and diastolic blood pressure (DBP) and plasma cortisol following oral AMPH (0.4 mg/kg) in male PGs (n=12) and HCs (n=11) who underwent a positron emission tomography (PET) scan. The Stop Signal Task enabled assessment of the link between physiological and behavioral dysregulation. Trait moderating effects were explored. The responses of PGs to AMPH differed from those of HCs on every index. PGs displayed persistent elevation in DBP and concomitant reduction in HR (i.e. baroreflex) compared to HCs beyond 90 min post-dose. PGs displayed deficits in cortisol compared to HCs that were partially reversed by AMPH. Impairment on the Stop Signal Task correlated positively with HR in controls, but negatively with HR in PGs, suggesting that strong initial and compensatory cardiac responses to a stimulant may each predict disinhibition. Extraversion predicted greater disinhibition in PGs. Noradrenergic disturbances may contribute to sensitized responses to stimulant challenge and disinhibition in PGs.

The role of ANKK1 and TTC12 genes on drinking behaviour in tobacco dependent subjects1

Abstract Objectives. Alcohol use disorders (AUD) act as a risk factor for smoking relapse, and tobacco dependent (TD) subjects with comorbid AUD experience more withdrawal symptoms compared to TD subjects without AUD or other psychiatric comorbidities. Our aim was to investigate whether drinking behaviour in the past 12 months and smoking relapse due to alcohol use in TD subjects was associated with polymorphisms flanking the TTC12/ANKK1/DRD2 region since associations have been found between these genes and AUD and TD as separate disorders. Methods. 380 TD subjects were assessed for alcohol use and relapse to smoking. Subjects were genotyped for polymorphisms located in the TTC12/ANKK1/DRD2 region. Results. Associations were found between ANKK1 haplotype rs4938015C_rs11604671A and age of onset of daily smoking, as well as with hazardous drinking. No genetic association was found with smoking relapse due to alcohol consumption. Conclusions. Our findings suggest that TD subjects who present earlier age at onset and carry this haplotype may have a higher risk for developing an alcohol use disorder.

Childhood Abuse History in Depression Predicts Better Response to Antidepressants with Higher Serotonin Transporter Affinity: A Pilot Investigation

Objectives: Childhood abuse is a powerful prognostic indicator in adults with major depressive disorder (MDD) and is associated with numerous biological risk factors for depression. The purpose of this investigation was to explore if antidepressant medication affinity for the serotonin transporter moderates the association between childhood abuse and treatment response. Methods: Our sample included 52 outpatients with MDD who had received up to 26 weeks of pharmacotherapy, stratifying antidepressant medications with a high versus a low affinity for the serotonin transporter. Patients completed the Hamilton Rating Scale for Depression, Beck Depression Inventory II, Home Environment Questionnaire, and Ontario Health Supplement: Child Abuse and Trauma Scale to assess depression and childhood abuse. Results: Medication class moderated the link between 3 indices of childhood abuse and treatment response such that higher levels of childhood abuse were associated with higher levels of depression severity after treatment only in those patients receiving antidepressant medications with a weak affinity for the serotonin transporter. Conclusions: This pilot study suggested that prolonged exposure to stress during childhood may result in biological vulnerabilities for depression, which may in turn be differentially targeted by pharmacological agents which target serotonin to a greater or lesser degree.