Gambling Addiction/ Pathological Gambling

Pathological gambling (PG) is the inability to fight the urge to gamble, despite severe consequences in personal, familial, and occupational domains. Of the few naturally occurring addictions or social addictions that exist, gambling seems to have one of the more directly repercussive effects on one’s life. First believed to be an Obsessive Compulsive Spectrum Disorder related disorder, research has recently revealed a stronger connection to addiction and impulse control disorders[1] . It may also be the case that gambling isn’t so black and white but rather, contains all three of these cases where they are all subtypes of pathological gambling, a theory that has obtained some recent empirical support[2] . The etiology of this addiction is hypoactive impulse control resulting from changes in centers of the brain such as the medial prefrontal cortex and orbitofrontal cortex. Underlying these changes, are all three major neurotransmitter pathways: the dopamine, serotonin, and norepinephrine pathways. Dopamine levels seem to relate to the type of impulses one has while gambling but the under- regulation of impulses is centered upon serotonin (5-HT) and may be predetermined at birth such as having the gene for the less functional serotonin polymorphism 5-HTTLPR[3] or it can be obtained behaviourally through repeated risk-taking endeavors. The research on gambling addictions is not as deep as other addictions research and has only recently seen a rapid growth in the literature. It focuses more on treatment then molecular causes or changes as they are likely analogous to normal learning mechanisms in the previously mentioned regions of the prefrontal cortex. As already stated, different subtypes may exist, each with its own dysregulation of neurotransmitters.

Biology of Pathological Gambling

Gambling_Illusions.jpg
Some illusory beliefs that pathological gamblers prescribe to which need to be dissolved through CBT.


Etiology in the Prefrontal Cortex

According to fMRI studies, lower levels of activity in the ventromedial frontal (VMF) cortex are involved in PG, impairing decisions that involve risks[4] . Lesion studies with patients on the Iowa gambling task have also implicated the orbitofrontal cortex (OFC) as a major contributor to pathological gambling and poor decision-making[5] . These lesion studies have found that the OFC has roles in assigning relative values to stimuli as well as making value-based judgments[6] . Eventually, this leads to overvaluing some illusory beliefs and selectively focusing on times of success.


Braaaaiiinnn.gif
Dopaminergic and serotonergic pathways in the brain.

Neurotransmitter Pathways

Gambling is a complex behaviour that involves impulsive moments, rewarding moments, and the thrill of awaiting the outcomes. As such, it affects the three main neurotransmitter pathways in the brain, serotonin, dopamine, and norepinephrine. The likely result of gambling on these systems is a hypersensitization to dopamine and norepinephrine and desensitization to serotonin. This means that less dopamine and norepinephrine is needed to activate their effects on the orbitofrontal and medial prefrontal cortex whereas more serotonin is needed for its effect.

Dopaminergic pathway

The dopaminergic system consists of four main pathways, two of which are implicated in PG; the nigrostriatal pathway that directs motivated motor control and the mesolimbic pathway that is involved with reward and salience. The pathway that PG is involved with is the mesolimbic pathway between the ventral tegmental area (VTA) and the nucleus accumbens and its associated mesocortical pathway toward frontal lobe regions. It has been shown that dopamine release is hyperactive in pathological gamblers, specifically due to increases in reward size and increases in uncertainty[7] [8] . These two factors are exacerbated by the very nature of gambling, especially if accompanied by the superstitious cognitions and beliefs that most PGs hold. They believe they will eventually win, extending the anticipation of reward and dopamine release. More dopamine output to the medial prefrontal and orbitofrontal regions of the brain coinciding with the lack of serotonin in those regions reinforces the lack of inhibition and thus, impulsive behaviour arises.

Serotonergic pathway

The serotonin pathway originates in the raphe nuclei of the brainstem. 5-HT is produced and transmitted throughout the cortical areas of the brain. It has many roles in mood, sleep, memory, and cognition but in the case of PG, its role lies in areas such as addiction, aggression, impulsivity, and anxiety. Serotonin plays roles in both excitatory and inhibitory transmission but considering the research, lower levels of serotonin mixed with impulsive behaviour is suggestive of an inhibitory role to control impulsive urges and aggression. Higher levels of serotonin on the other hand, seem to be related to addictive behaviours and anxiety[9] .

Adrenergic pathway

Although the adrenaline (norepinephrine) system is involved in pathological gambling, the research has not found much conclusive evidence that it is a root cause of PG but rather many believe it to be a result of it. The thrill seeking aspect of gambling seems to be more of a cognition that arises from pathological gamblers to rationalize their addictions, which seems likely as there are many more thrilling activities aside from gambling that don’t involve dramatic financial costs.

Sex Differences

The idea that sex differences exist in pathological gamblers is highly controversial. Although it has been observed that men prefer table games such as poker and blackjack while women prefer solitary games such as slots and the lottery, it is not clear whether this is due to social or biological reasons. Some evidence has arisen for the biological argument such as higher testosterone levels producing more antisocial behaviour, aggression, and impulsivity[10] but it is not conclusive of whether this was an inherent effect of testosterone or just a social influence that poker, blackjack, and other table games are men's games. This is, however, backed up with even stronger evidence coming from the genetics literature on PG buts since the roles of the genes have not been completely explored, no conclusive statements about sex differences can be made.

Treatment


Pharmacological Treatments

Treatment for gambling addictions through pharmacological intervention has been controversial. Treatments were selected based on how PG resembled other disorders such as OCD, addiction, and impulsivity disorders and so, SSRIs, anti-addiction drugs, and mood stabilizers were all used in drug trials but showed inconsistent results[11] . This controversy likely lies in the nature of the disorder, which has recently been theorized to contain three different subtypes[12] [13] . This inconsistency means that the best course of action thus far has been to combine these drugs with cognitive behavioural therapy[14] . Although treating the underlying causes of PG have been inconsistent, opioid agonists (pain killers) such as nalmefene and naltrexone have been shown to be effective craving relievers and work well to treat PG[15] .
Recently, drug trials have been introduced to rats after developing a useful animal model, the rat gambling task (rGT) that has been found to resemble human behaviour in the Iowa gambling task (IGT)[16] . This was an important step considering the lack of patients and the unknown interactions of each drug on pathological gamblers. To more specifically identify the root causes of PG, rat trials have been implemented in order to uncover causes at the molecular level by targeting specific receptors and by both increasing and decreasing neurotransmitters.

Drugs.jpg
Parkinson's drug treatments.
Dopamine (DA)

A number of dopamine agonists have been used such as amphetamines, SKF 81297, and Quinpirole to assess DA’s role in PG[17] . Amphetamines are non-selective DA agonists and target all of the DA receptors. As the dosage increased, the rats shifted choice behaviour toward smaller rewards with smaller and less frequent punishments and prefer to more constantly win regardless of if they could win more. Quinpirole which is a DA receptor D2/D3 agonist, and SKF 81297 which is a DA receptor D1 agonist did not change behaviour in the rIGT but did affect simpler versions, leading to the conclusion that both of these groups of receptors need to be activated for PG to arise.
A dopamine D2 receptor antagonist, Eticlopride has also shown that DA is involved in PG[18] . Mild doses of Eticlopride were able to decrease the amount of rats that would take big risks and instead select the best option. This is, however, contradicted by another study that showed BCAA, a drug that also decreases DA levels to have the opposite effect in normal humans, leading to more high-risk choices on the IGT[19] . This may seem like contradictory research but the levels of baseline DA are different for these populations and the data actually converges to suggest there is an optimal level of DA. This level of dopamine leads to selecting optimal choices on the IGT, whereas lower or higher levels of DA may lead to emotional distress, cognitive impairment, and then failure on the IGT.
These results overall seem to suggest that more DA release will lead to an addictive type of behaviour while the lack of DA in the brain will lead to impulsive, high risk behavioural choices in order to obtain higher reward to compensate for the lack of DA.

Parkinson's disease

PD is a debilitating disease that results in the erosion of the substantia nigra, an area responsible for the production of dopamine in the nigrostriatal pathway. This results in a dysfunction in motor control. To resolve this, taking dopamine agonists such as pramipexole and ropinirole can successfully restore motor function but practically all the DA agonists have been implicated in comorbid pathological gambling[20] . PG is normally comorbid with 3.4% of PD patients but for those on DA agonist drugs, this rises to 7.2%[21] . Recommendations are to stop DA agonist treatment but if motor function deteriorates again a combination of DA agonists and other PG treatments like opiate agonists may be more beneficial.

Serotonin (5-HT)

Serotonin agonists have also been tested such as the 8-OH-DPAT that targets 5HT1A receptors[22] . This drug was able to lead to less impulsive decisions with less selection of higher risk choices but it also avoided the best selection. This is likely a result of becoming overly inhibited and selecting the safest option all the time, leading to an overall loss on the task. This drug treatment was also accompanied with slowed motor output, decreased number of trials within the time limit, and increased latency to collect food.
A 5HT1A receptor antagonist, WAY 100635, has also been tested but showed no significant effect alone but did show an interaction effect when co-administered with 8-OH-DPAT[23] . It was able to nullify all effects of the 5HT agonist, treating the associated PG symptoms.
The overall results of the serotonin trials are suggestive that the rats likely suffered from an anxiety disorder as they were slower in their selections, waited longer in between trials, seemed to cautiously approach their reward (food pellets), and chose safer options. Whether this is true or not is inconclusive but it draws connections to the OCD theory behind PG.

Cognitive Behavioural Therapy (CBT)

As far as treating pathological gambling goes, cognitive behavioural therapy is definitively the best option right now. Considering the inconsistency of drug treatments and the diversity in how the disorder manifests, this shouldn’t be too much of a surprise. By dispelling the illusory beliefs behind gambling and working on their addictions with drug treatment, combined CBT with drug therapy shows the best results for treating PG[24] .

Theories of Pathological Gambling


Addictions Model

The dominant theory underlying PG is the addiction model[25] . Although it was originally based on OCD, a growth in research suggests that PG more resembles a substance-abuse disorder. Brain imaging has detected similar activation in medial prefrontal and orbitofrontal regions of the brain as substance-dependent addicts and similar behavioural outcomes.

Theoretical Subtypes Model

Another model that has arisen is the Theoretical Subtypes model that assumes a variety of pathological gamblers[26] . The majority of research has found PG to be most similar to addictions but this doesn’t mean the other models should be disregarded. In fact, PG has been found to resemble three types of disorders: the OCD model, addictions model and impulse-control disorder model. Considering the inconsistencies in drug treatment and the fact that there are different types of gamblers that play different types of games, there are likely different clusters of gamblers that follow different strategies and thus, have different underlying dysfunctions.
Treating_subtypes.jpg
Iancu, I., Lowengrub, K., Dembinsky, Y., Kotler, M., & Dannon, P. N. Pathological gambling: An update on neuropathophysiology and pharmacotherapy. CNS Drugs 22(2): 123-138 (2008).

Gene Candidates

Little of the research is conclusive just as the treatment research and there is even belief that PG may have gender differences in its etiology. Despite this, some genes have been given special attention in their relation to PG. A T/C substitution 800 bp from exon I in the DRD1 gene (DRD1-800 T/C allele T) has been associated with PG[27] . Another gene thought responsible for PG is the shorter 5-HTTLPR gene variant of the serotonin transporter, making it less functional and decreasing serotonin efficiency[28] . Similar to this, repeats in the DRD4 gene in females and MAO-A gene in males that produce less functional receptors have also been implicated. Another prominent gene candidate is the Taq-A1 allele of the DRD2 gene that has been associated with impulsive-addictive-compulsive behaviours.


References

  1. ^
    Westphal, J.R. Pathological gambling: Psychiatric models. Int J Ment Health Addiction 6, 602–618 (2008).
  2. ^ Zeeb, F. D., Robbins, T. W., & Winstanley, C.A. Serotonergic and dopaminergic modulation of gambling behavior as assessed using a novel rat gambling task.
    Neuropsychopharmacology 34, 2329-2343 (2009).
  3. ^ Homberg, J.R., van den Bos, R., den Heijer, E., Suer, R., & Cuppen, E. Serotonin transporter dosage modulates long-term decision-making in rat and human.
    Neuropharmacology 55, 80-84 (2008).
  4. ^
    Tanabe, J., Thompson, L., Claus, E., Dalwani, M., Hutchison, K., & Banich, M. T. Prefrontal cortex activity is reduced in gambling and nongambling substance users during decision-making. Human Brain Mapping 28: 1276-1286 (2007).
  5. ^ Bechara, A. et al. Deciding advantageously before knowing the advantageous strategy. Science 275: 1293–1295 (1997).
  6. ^ Fellows, L. K. The role of the orbitofrontal cortex in decision making. Ann. N.Y. Acad. Sci. 1121: 421-430 (2007). doi: 10.1196/annals.1401.023
  7. ^
    Schultz, W., Preuschoff, K., Camerer, C., Hsu, M., Fiorillo, C. D., Tobler, P. N., & Bossaerts, P. Explicit neural signals reflecting reward uncertainty. Philosophical Transactions: Biological Sciences 363(1511): 3801-3811 (2008).
  8. ^ Richardson, N. R. & Gratton, A. Changes in nucleus accumbens dopamine transmission associated with fixed- and variable-time schedule-induced feeding. European Journal of Neuroscience 27: 2714-2723 (2008). doi:10.1111/j.1460-9568.2008.06236.x
  9. ^
    see above [2]
  10. ^
    Stenstrom, E. & Saad, G. Testosterone, financial risk-taking, and pathological gambling. Journal of Neuroscience, Psychology, and Economics 4(4): 254-266. (2011).
  11. ^
    see above [1]
  12. ^ Iancu, I., Lowengrub, K., Dembinsky, Y., Kotler, M., & Dannon, P. N. Pathological gambling: An update on neuropathophysiology and pharmacotherapy. CNS Drugs 22(2): 123-138 (2008).
  13. ^ Potenza, M. N., Sofuoglu, M., Carroll, K. M., & Rounsaville, B. J. Neuroscience of behavioral and pharmacological treatments for addictions. Neuron 69: 695-712 (2011).
  14. ^ see above [13]
  15. ^ Grant, J. E., Potenza, M. N., Hollander, E., Cunningham-Williams, R., Nurminen, T., Smits, & G., Kllio, A. Multicenter investigation of the opioid antagonist nalmefene in the treatment of pathological gambling. Am J Psychiatry 163 (2): 303-312 (2006).
  16. ^
    see above [2]
  17. ^
    see above [2]
  18. ^
    see above [2]
  19. ^ Sevy, S., Hassoun, Y., Bechara, A., Yechiam, E., Napolitano, B., Burdick, K., Delman, H., & Malhotra, A. Emotion-based decision-making in healthy subjects: Short-term effects of reducing dopamine levels. Psychopharmacology 188: 228-235 (2006).
  20. ^
    Dodd, M. L., Klos, K. J., Bower, J. H., Geda, Y. E., Josephs, K. A., & Ahlskog, E. Pathological gambling caused by drugs used to treat Parkinson disease. Arch Neurol 62: 1377-1381 (2005).
  21. ^ Wong, S. H. & Steiger, M. J. Pathological gambling in Parkinson’s disease: Reducing or stopping dopamine agonists may help. BMJ 334: 810-811 (2007). doi:10.1136/bmj.39176.363958.80
  22. ^
    see above [2]
  23. ^
    see above [2]
  24. ^
    see above [13]
  25. ^
    see above [1]
  26. ^
    see above [12]
  27. ^
    Sabbatini da Silva Lobo, D., Vallada, H. P., Knight, J., Martins, S. S., Tavares, H., Gentil, V.,& Kennedy, J. L. Dopamine genes and pathological gambling in discordant sib-pairs. J Gambl Stud 23: 421–433 (2007). doi: 10.1007/s10899-007-9060-x
  28. ^ Ibáñez, A., Blanco, C., Perez de Castro, I., Fernandez-Piqueras, J., Sáiz-Ruiz, J. Genetics of Pathological Gambling. J Gambl Stud 19 (1): 11-22 (2003).

Biology of PGTreatment for gambling addictions through pharmacological intervention has been controversial. Treatments were selected based on how PG resembled other disorders such as OCD, addiction, and impulsivity disorders and so, SSRIs, anti-addiction drugs, and mood stabilizers were all used in drug trials but showed inconsistent results1. This controversy likely lies in the nature of the disorder, which has recently been theorized to contain three different subtypes[9],[10]. This inconsistency means that the best course of action thus far has been to combine these drugs with cognitive behavioural therapy10. Although treating the underlying causes of PG have been inconsistent, opioid agonists (pain killers) such as nalmefene and naltrexone have been shown to be effective craving relievers and work well to treat PG11.Recently, drug trials have been introduced to rats after developing a useful animal model, the rat gambling task (rGT) that has been found to resemble human behaviour in the Iowa gambling task (IGT)2. This was an important step considering the lack of patients and the unknown interactions of each drug on pathological gamblers. To more specifically identify the root causes of PG, rat trials have been implemented in order to uncover causes at the molecular level by targeting specific receptors and by both increasing and decreasing neurotransmitters.