Increased Striatal Dopamine Synthesis Capacity in Gambling Addiction

Increased Striatal Dopamine Synthesis Capacity in Gambling Addiction Studies

Abstract & Background

• Central Hypothesis: Dopamine plays a crucial role in the pathophysiology of pathological gambling (PG).

• Previous Research Context:

  • Behavioral, cognitive, and neurobiological profiles of individuals with PG resemble those with substance use disorder (SUD), particularly stimulant addiction.

  • Pathological gambling was reclassified as an addiction disorder in the DSM-5.

  • Dopamine in SUDs:

    • Characterized by a decrease in striatal dopamine D2/D3 receptor availability, more consistently in stimulant users.

      • Evidenced by cross-sectional studies using $[^{11}C]raclopride$ PET and SPECT imaging.

    • Dopamine synthesis capacity (measured with $[^{18}F]DOPA$ PET) in SUDs has shown either low or unaltered levels.

    • Longitudinal animal studies indicate diminished baseline striatal D2/D3 receptor availability predicts and is a consequence of continued drug use (e.g., lower D2/D3 in drug-naive monkeys predicts higher cocaine self-administration, reduced binding after repeated exposure).

    • High impulsivity traits are associated with low dopamine D2/D3 receptor availability and predispose to drug addiction in rats.

    • Human studies link trait impulsivity to addiction vulnerability, but the direction of association with dopamine D2/D3 receptors is less clear, with both positive and negative correlations reported in healthy controls (HCs) and methamphetamine users.

  • Dopamine in Pathological Gambling (Prior to this Study):

    • All previous PET studies in PG failed to reveal abnormal dopamine D2/D3 receptor availability compared to HCs.

    • Two studies found a negative correlation between baseline ventral striatum D2/D3 receptor binding and trait impulsivity in PGs.

    • Gambling-induced dopamine release studies showed no overall group differences but correlations with gambling severity, excitement, and performance.

    • Direct evidence for abnormal dopamine function primarily came from studies showing altered responsiveness to dopaminergic drugs.

      • PGs displayed greater amphetamine-induced dopamine release in the dorsal striatum (measured with PET using $[^{11}C]$-(1)-4-Propyl-9-hydroxynaphthoxazine) compared to HCs.

      • This echoes clinical observations in Parkinson's disease where dopaminergic treatment can induce gambling disorder symptoms.

    • There was a paucity of research on dopamine synthesis capacity in PGs, with only one recent study reporting no difference with HCs.

    • Increased dopamine synthesis capacity has been associated with increased behavioral disinhibition and financial extravagance in healthy subjects and Parkinson's patients.

• Current Study Objective: To investigate striatal dopamine synthesis capacity in male PGs and HCs using dynamic $[^{18}F]DOPA$ PET imaging, matched for age, education, and verbal IQ.

Methods and Materials

Subjects

• Recruitment: Initially 15 PGs and 15 HCs recruited.

  • 13 PGs and all HCs participated in a previous pharmaco-fMRI study.

  • 2 PGs were newly recruited.

  • PGs recruited via advertisement and addiction treatment centers; reported being unmedicated/untreated for gambling at the time of PET.

  • HCs recruited via advertisement.

• Psychiatric Assessment & Exclusion Criteria:

  • Structured psychiatric interview (Mini-International Neuropsychiatric Interview–Plus) administered to all by a medical doctor or clinical psychologist.

  • Exclusion: Lifetime history of schizophrenia, bipolar disorder, ADHD, autism, bulimia, anorexia, anxiety disorder, obsessive-compulsive disorder; past 6-month history of major depressive episode.

  • Substance Use Exclusion: Current or past-year SUD (assessed with 10-item Drug Abuse Screening Test questionnaire).

    • Data from 2 PGs were excluded for past-year cannabis dependence (one also had past cocaine dependence).

    • One included PG had histories of alcohol (ended 8 years prior) and cocaine (ended 15 years prior) dependence.

    • None of the other PGs or HCs had SUD history.

  • Other Exclusions: Current psychiatric treatment, psychotropic medication use, daily alcohol intake > 4 beverages.

• Pathological Gambling Criteria: All gamblers met $\ge 5$ DSM-IV-TR criteria for pathological gambling and were otherwise healthy.

  • 4 PGs had cognitive behavioral treatment $2-6$ years before the PET study.

  • Gambling Severity (SOGS):

    • Minimum lifetime SOGS score of $5$ (range $= 5-18$) for PGs upon initial inclusion.

    • HCs generally had a SOGS score of $0$ (except 2 with $1$ and $2$).

    • Scores reassessed at PET study: past-year SOGS range $= 5-11$, past-3-month SOGS range $= 0-10$.

  • Frequent Forms of Gambling (at least once a week for money):

    • Slot machines ($53\%$),

    • Card games ($46\%$),

    • Casino games ($33\%$),

    • Sports betting ($40\%$),

    • Lotteries ($40\%$),

    • Stock market ($7\%$),

    • Bowling, pool, golf, darts, etc. ($7\%$).

Study Procedure

• Delay: $5$ to $29$ months (median $= 23.5$ months) between previous fMRI and current PET study.

• Preparation: Subjects received 150 \text{ mg}$ of carbidopa and 400 \text{ mg}$ of entacapone approximately 1 \text{ hour}$ before PET scan to reduce peripheral [^{18}F]DOPA metabolism and increase brain tracer availability without psychotropic side effects.

• Self-Report Measures (on PET day): Past-year & past-3-month SOGS, Gamblers’ Beliefs Questionnaire (GBQ), revised Barratt Impulsiveness Scale (BIS-11).

Imaging Acquisition

• MRI Scan: High-resolution anatomical T1-weighted MRI (Siemens 3 \text{T}$ MR scanner) for coregistration with PET data.

  • Parameters: Repetition time $= 2300 \text{ ms}$, echo time $= 3.03 \text{ ms}$, $8^\circ$ flip angle, $192$ sagittal slices, slice-matrix size $= 256 \times 256$, voxel size $= 1 \times 1 \times 1 \text{ mm}^3$).

• PET Acquisition (Siemens mCT PET/CT camera):

  • Low-dose CT scan for attenuation correction.

  • 89\text{-minute}$ dynamic PET scan initiated simultaneously with bolus injection of [^{18}F]DOPA$into an antecubital vein.</p></li><li><p>Reconstruction: Ordered subset expectation maximization algorithm with weighted attenuation and time-of-flight recovery, scatter-corrected, and smoothed with a$4 \text{-mm}$ full width at half maximum kernel.

Regions of Interest (ROIs)

• Hand-drawn in native space based on individual structural MRI, using Mango software.

• Striatal ROIs: Dorsal putamen, caudate head, ventral striatum (including nucleus accumbens, ventral caudate, ventral putamen), and caudate body (dorsal caudate posterior to anterior commissure).

• Reference Region: Cerebellar gray matter, delineated by FreeSurfer automatic segmentation.

  • Only the posterior three-fourths of the cerebellum included to avoid contamination from midbrain $[^{18}F]DOPA$ signal.

PET Analysis

• $[^{18}F]DOPA$ images realigned to the $11^{th}$ frame (middle) for motion correction (using SPM8).

• Mean $[^{18}F]DOPA$ image and realigned frames coregistered to structural MRI (using SPM8).

• Uptake ($K_i$) Images: Generated using an in-house graphical analysis program implementing Patlak plotting.

  • Represent tracer accumulation in ROIs relative to cerebellar reference region.

  • Generated from PET frames corresponding to $24$ to $89$ minutes.

  • Comparable to $K_i$ images obtained with a blood input function, but scaled to tracer volume of distribution in the reference region.

• Statistical Comparisons:

  • Group comparisons of $K_i$ values used repeated-measures ANOVAs with group (between-subject) and bilateral (averaged) ROIs (within-subject).

  • Greenhouse–Geisser correction applied for sphericity violations.

  • Post hoc simple main effects of group in various ROIs used FDR-corrected $p = .05$ for multiple comparisons.

  • Same strategy for ROI volume comparisons.

• Correlations in PGs: Pearson correlations (FDR-corrected $p = .05$) between $K_i$ values in the 4 ROIs and gambling severity (SOGS), impulsivity (BIS-11), and gambling cognitive distortions (GBQ).

Results

Subject Characteristics and Traits

• Matching: Groups were matched for age, body mass index (BMI), net income, and verbal IQ (Dutch version of National Adult Reading Test).

  • Age: HCs $36.20 \pm 11.63$, PGs $40.92 \pm 6.70$ ($p = .209$).

  • Verbal IQ: HCs $104.93 \pm 9.17$, PGs $101.38 \pm 11.05$ ($p = .361$).

  • Income: HCs $1648.66 \pm 1037.73$, PGs $1650.00 \pm 1038.54$ ($p = .487$).

  • BMI: HCs $23.85 \pm 3.12$, PGs $24.06 \pm 1.90$ ($p = .840$).

• Significant Differences (on PET testing day):

  • Impulsivity (BIS-11): PGs significantly higher ($73.25 \pm 10.14$) than HCs ($58.07 \pm 8.33$) ($p < .001$).

  • SOGS, Past Year: PGs significantly higher ($9.15 \pm 1.63$) than HCs ($0.40 \pm 0.83$) ($p < .001$).

  • SOGS, Past 3 Months: PGs significantly higher ($3.23 \pm 3.39$) than HCs ($0.06 \pm 0.26$) ($p < .001$).

  • Gambling Distortions (GBQ–Total): PGs significantly higher ($90.77 \pm 30.94$) than HCs ($47.71 \pm 21.59$) ($p < .001$).

  • Number of Smokers: HCs $2$, PGs $5$ ($p = .257$).

  • Alcohol Use Disorders Identification Test (AUDIT): PGs $6.69 \pm 3.86$, HCs $6.00 \pm 3.78$ ($p = .636$); $5$ subjects in each group scored $\ge 8$.

PET Measures (Dopamine Synthesis Capacity)

• Overall $K_i$ Differences:

  • Significant difference in mean $K<em>i$ between ROIs ($F</em>{3,78} = 122.95$, $p < .001$, Cohen's $d = 4.34$).

  • Significant difference in mean $K<em>i$ between groups ($F</em>{1,26} = 6.01$, $p = .021$, Cohen's $d = 0.965$).

  • Group $\times$ ROI interaction approached significance ($F_{3,78} = 3.139$, $p = .051$, Cohen's $d = 0.695$).

• Simple Main Effects of Group (non-PVC ROIs):

  • Caudate body: $K<em>i$ $16\%$ higher in PGs ($F</em>{1,27} = 5.301$, $p_{FDR} = .040$).

  • Dorsal putamen: $K<em>i$ $18\%$ higher in PGs ($F</em>{1,27} = 8.047$, $p_{FDR} = .012$).

  • Ventral striatum: $K<em>i$ $17\%$ higher in PGs ($F</em>{1,27} = 6.312$, $p_{FDR} = .025$).

  • Caudate head: No significant difference, $9\%$ higher in PGs ($F<em>{1,27} = 1.435$, $p</em>{FDR} = .323$).

• Sensitivity Analyses:

  • ROI Volume: Total number of voxels within all ROIs not significantly different between groups ($F_{1,25} = 0.174$, $p = .680$).

    • Significant difference between ROIs ($F<em>{3,78} = 304.39$, $p < .001$) and group $\times$ ROI interaction ($F</em>{3,78} = 3.586$, $p = .028$).

    • Only ventral striatum ROI had more voxels in PGs ($F<em>{1,27} = 8.457$, $p</em>{FDR} = .028$).

    • $K<em>i$ values were not correlated with ROI volume in any ROI ($p > .065$ for all), indicating volume differences did not drive $K</em>i$ group differences.

  • Partial Volume Correction (PVC):

    • Repeated-measures ANOVA with PVC ROIs showed a significant main effect of group ($F<em>{1,26} = 4.230$, $p = .050$) and PVC ROI ($F</em>{3,24} = 76.186$, $p < .001$).

    • Significant Group $\times$ PVC ROI interaction ($F_{3,24} = 3.205$, $p = .041$).

    • Post hoc tests: $K<em>i$ values only significantly higher in PGs in the dorsal putamen ($F</em>{1,27} = 7.200$, $p = .013$).

    • No group differences in caudate body ($F<em>{1,27} = 2.390$, $p = .134$), caudate head ($F</em>{1,27} = 3.128$, $p = .089$), or ventral striatum ($F_{1,27} = 2.905$, $p = .100$) with PVC.

  • Comorbid Cannabis Dependence: Analyses including the 2 excluded PGs showed qualitatively similar, but weaker, results.

Correlations in PGs

• Gambling-Related Cognitive Distortions (GBQ):

  • Significant positive correlation with $K<em>i$ values in the dorsal putamen ($r = .595$, $p</em>{FDR} = .043$).

  • Significant positive correlation with $K<em>i$ values in the caudate head ($r = .601$, $p</em>{FDR} = .040$).

• Gambling Severity (SOGS): No significant correlation with $K_i$ values in any ROI.

• Impulsivity (revised Barratt Impulsiveness Scale): No significant correlation with $K_i$ values in any ROI.

Discussion

• Key Finding: First empirical evidence for increased striatal dopamine synthesis capacity in pathological gambling.

• Consistency with Previous Research:

  • Aligns with increased dorsal striatal dopamine release in PGs after amphetamine administration.

  • Consistent with positive correlation between dopamine release and subjective excitement/gambling severity in the ventral striatum during gambling.

  • Agrees with reports of greater reward-induced dopamine release in Parkinson's disease patients with treatment-induced pathological gambling.

• Link to Cognitive Distortions: Higher dopamine synthesis capacity in the dorsal putamen and caudate head positively correlated with the severity of gambling-related cognitive distortions in PGs.

  • Cognitive distortions are a key characteristic of PG, predicting severity, play duration, and treatment outcome.

  • Supports idea that enhanced dopaminergic transmission is a biological substrate of PG.

• Contrast with Substance Use Disorders (SUDs):

  • Increased dopamine synthesis capacity in PGs remarkably contrasts with low or unaltered capacity found in SUDs (except for 1 previous PG study). This could reflect variability in presynaptic dopamine cell injury or differences in drug-induced neuroplasticity in SUDs.

  • Possible Explanation for Difference: Absence of substance-specific confounds (e.g., drug toxicity on the dopamine system) in PG, highlighting its potential for studying dopamine's role in addiction without exogenous substances.

  • Alternative: PG might not be as similar to stimulant addiction as previously thought, or addiction itself is a multi-neurotransmitter disorder with varying dopamine abnormalities across different SUDs.

• Interplay of Dopamine System Components:

  • Given the positive relationship between dopamine synthesis capacity and dopamine release, and the negative relationship between synthesis capacity and D2/D3 receptor availability (in HCs), current results suggest increased striatal dopamine release and reduced D2/D3 receptor availability in PG may reflect increased dopamine synthesis capacity.

• Discrepancy with Majuri et al. (2017) Study: Another $[^{18}F]DOPA$ PET study found no difference in dopamine synthesis abnormality in PGs.

  • Speculated Reasons: Differences in drug dependence history (e.g., higher incidence of smoking in Majuri's study, as nicotine/drugs can affect dopamine synthesis capacity); heterogeneity among PGs (different subtypes gambling for different motives, e.g., coping with negative affect vs. enhancing positive affect).

• Dorsal Striatum Involvement:

  • Most consistent finding of heightened dopamine synthesis capacity in PGs in the dorsal striatum (dorsal putamen and caudate body).

  • Overlaps with location of increased amphetamine-induced dopamine release in PGs.

  • Role: Dorsal striatum is crucial for habitual control of behavior.

  • Connection to Incentive Sensitization: Increased dorsal putamen dopamine synthesis fits with incentive sensitization theories where the dorsal putamen becomes progressively involved after repeated exposure to stimulants.

  • Vulnerability: This increased dopamine response to rewarding stimuli could reflect an addiction vulnerability and/or a consequence of addictive behavior, driving excessive reward-seeking.

• Causality: The study was not designed to determine if alterations in dopamine synthesis capacity are a direct cause or consequence of PG.

  • Potential Origin: Genetic factors affecting dopamine synthesis pathway (e.g., dopa decarboxylase gene variants) might play a role.

Limitations

• Sample Size and Gender: Small sample, only male subjects. This homogeneity reduced confounds but limits generalizability.

• Clinical Assessments Timing: With the exception of current/past-year drug dependence, other clinical assessments were performed ~23.5 months prior to PET study, potentially affecting current symptom scores.

• Alcohol Use: Similar numbers of subjects in both groups (5 HCs, 5 PGs) scored $\ge 8$ on AUDIT, indicating possible alcohol problems, but groups did not differ on scores, so unlikely to influence main findings.

• Acuity of Gambling Problems: Only 4 of 13 PGs experienced acute gambling problems (SOGS $> 5$ past 3 months) at time of scan. Increased dopamine synthesis capacity might reflect a vulnerability rather than a consequence of current problems, given its thought to be a stable measure.

• Partial Volume Correction (PVC) Impact:

  • Initially robust differences in non-PVC ROIs (dorsal putamen, caudate body, ventral striatum).

  • With PVC, difference was less striking, significant only in the dorsal putamen (also for atlas-based ROIs).

  • PVC incorporates ROI size/shape and proximity to white matter/cerebral spinal fluid.

  • Caveat: PVC methods can amplify noise and increase variance, potentially reducing sensitivity.

  • Despite this, robust findings of higher dopamine synthesis capacity in the dorsal putamen are believed to be reliable.

Clinical Implications

• Potential Treatment Targets: Results suggest reducing dopamine levels might be beneficial in PG.

• Current Pharmacological Challenges:

  • Atypical antipsychotic olanzapine (dopamine/serotonin antagonist) showed no benefit over placebo in two trials.

  • Bupropion (dopamine/norepinephrine transporter inhibitor) also showed no benefit.

  • Dopamine D2/D3 receptor antagonists (sulpiride, haloperidol) yielded inconclusive results.

  • A small single-blind study using D1 receptor antagonist ecopipam showed significant reductions in gambling severity.

  • More research needed to assess effectiveness of striatal dopamine receptor blockade.

• Complexity of Addiction: Addiction is a complex interplay of behaviors/cognitions, with heterogeneity among patients, types of drugs/games, suggesting a single neurotransmitter is unlikely to explain all aspects.

Acknowledgments and Disclosures

• Funding from Netherlands Research Organization grants (Rubicon, Veni, Vici) and James McDonnell scholar award.

• WJJ reports consultancies with Genentech, Novartis, and Bioclinica. All others report no biomedical financial interests or conflicts of interest.

References

• Numerous references cited throughout the text, supporting various claims regarding D2/D3 receptor availability in SUDs, impulsivity, previous PG studies, neurobiology of addiction, and methodological details.