Neurobiology of gambling disorder and alcohol use disorder comorbidity : preclinical study

Gambling disorder is considered a behavioral addiction that combines reward with executive decision-making processes in a complex and fascinating way. Gambling disorder overlaps with various psychiatric diseases, and comorbidity with alcohol use disorder and other substance use disorders is significant in its etiology. As in drug addictions, the dopaminergic mechanisms play a significant role in the neurobiology of gambling disorder. Clinical studies with opioid antagonist naltrexone also suggest that the opioidergic mechanism may have a role in modulating gambling behavior, especially in the gambler subgroup with a family history of alcoholism. Currently, treatment of gambling disorder mostly relies on psychotherapeutic approaches, and no significant achievements in drug development have been made. The main aim of the research was to validate a preclinical model of probability-based risky decision-making and investigate differences in dopaminergic and opioidergic mechanisms in decision-making behavior between AA (Alko Alcohol) and Wistar rats. The additional aim was to clarify the role of the nucleus accumbens in risky decision-making and develop a model to screen drug targets in gambling disorder. AA rats were used to represent a group of individuals with a genetic preference for alcohol use disorder, and a standard laboratory rat strain, Wistar, was chosen to represent the normal heterogenic population of gamblers. The decision-making of rats was studied in a probabilistic discounting task, which allows us to examine rats’ behavior at different levels of uncertainty. In the task, rats went through operant lever pressing training where different sized sucrose rewards guided the lever choices. The probability of gaining rewards changed slowly to a level where choosing the smaller reward was the most profitable option. After training, the effects of dopaminergic and opioidergic drugs on decision-making behavior were studied. In this research, we completed the aim to validate an animal model for studying the probability-based risky decision-making behavior and showed that D-amphetamine acts as a valid promoter for “gambling-like” behavior in rats. Results indicate that dopaminergic modulation of probability-based risky decision-making is pronounced in AA rats compared to Wistar. In the case of the opioidergic mechanisms, the results were ambiguous, and thus exact predictions of the relevance of opioids could not be made based on this study. The role of nucleus accumbens dopaminergic functions as a modulator of risky decisions was verified, but naltrexone’s effect on reducing risky decisions failed to show any promising results, indicating that the role of the opioid antagonist in the pharmacotherapy of gambling disorder is focused more on decreasing the overall motivation to gamble than modulating the risky decision-making in gambling. These studies create a platform for future studies aiming to point out the specific neurobiological mechanisms that control the behavior of the gambler subgroup with a genetic vulnerability to alcohol use disorder.Rahapeliriippuvuus on toiminnallinen riippuvuus, jossa aivojen palkitsemismekanismit yhdistyvät päätöksentekoprosesseihin monimutkaisella ja kiehtovalla tavalla. Rahapeliriippuvuuden komorbiditeetti useiden psykiatristen sairauksien sekä alkoholi- ja päihderiippuvuuksien kanssa on merkittävä. Kuten päihderiippuvuuksissa, aivojen dopamiinijärjestelmä näyttelee merkittävää osaa rahapeliriippuvuuden neurobiologiassa. Lisäksi kliiniset tutkimukset opioidiantagonisteilla viittaavat siihen, että myös aivojen opioidijärjestelmällä on osuutta pelaamiskäyttäytymisen säätelyssä, etenkin yksilöillä, joilla on geneettinen alttius alkoholiriippuvuudelle. Tällä hetkellä rahapeliriippuvuuden hoito perustuu psykoterapeuttisiin menetelmiin, eikä lääkekehityksessä ole saavutettu merkittäviä edistysaskelia. Tutkimuksen päätavoitteena oli validoida riskipäätöksenteon prekliininen malli ja tutkia dopaminergisten ja opioidergisten mekanismien eroavaisuuksia runsaasti alkoholia juovien AA-rottien ja tavallisten Wistar-rottien riskipäätöksenteko-käyttäytymisessä. Lisätavoitteena oli selventää accumbens-tumakkeen roolia näissä prosesseissa ja kehittää mallia pidemmälle lääkeainekandidaattien seulomiseksi. AA rotat valittiin mallintamaan yksilöitä, jolla on geeneettinen alttius alkoholiriippuvuudelle ja Wistar rotat valittiin puolestaan edustamaan heterogeenistä populaatiota. Rottien päätöksentekokäyttäytymistä tutkittiin laskevan todennäköisyyden mallilla, joka mahdollistaa päätöksenteko-käyttäytymisen tarkastelun eri todennäköisyyksien asteilla. Mallin perustavanlaatuinen idea on, että rotat opetetaan suorittamaan itseannostelua laskennallisesti eriarvoisten sokeripalkintojen avulla. Kun rotat oppivat suoriutumaan itseannostelusta tavalla joka vertautuu ihmisten päätöksentekoon vastaavissa todennäköisyystilanteissa, voidaan lääkeaineiden vaikutusta tutkia tähän käyttäytymiseen. Tutkimuksen tavoite mallin validoinnissa onnistui ja osoitimme että aivojen dopamiinimekanismeja aktivoiva D-amfetamiini toimii luotettavana riskipäätöksenteon modulaattorina. Tulokset viittaavat siihen, että AA rotilla päätöksentekoprosessien dopaminerginen säätely on korostunutta verrattuna Wistar rottiin. Lisäksi vahvistimme accumbens-tumakkeen dopaminergisten mekanismien roolin AA-rottien riskipäätösten säätelyssä. Opioidergisten mekanismien osalta tulokset viittavat opioidiantagonisti naltreksonin roolin olevan riskipäätöstentekoprosesseissa vähäinen ja että sen teho rahapeliriippuvuuden hoidossa perustuu todennäköisesti yksinomaan rahapelihimoa vähentävään vaikutukseen. Tutkimuksen tulokset luovat pohjan tuleville tutkimuksille joissa voidaan syventyä spesifisiin neurobiologisiin mekanismeihin jotka säätelevät alkoholiriippuvuudelle geneettisesti alttiiden rahapeliriippuvaisten pelaamiskäyttäytymistä

Dopaminergic modulation of reward-guided decision making in alcohol-preferring AA rats

R**esults from animal gambling models have highlighted the importance of dopaminergic neurotransmission in modulating decision making when large sucrose rewards are combined with uncertainty. The majority of these models use food restriction as a tool to motivate animals to accomplish operant behavioral tasks, in which sucrose is used as a reward. As enhanced motivation to obtain sucrose due to hunger may impact its reward-seeking effect, we wanted to examine the decision-making behavior of rats in a situation where rats were fed ad libitum. For this purpose, we chose alcohol-preferring AA (alko alcohol) rats, as these rats have been shown to have high preference for sweet agents. In the present study, AA rats were trained to self-administer sucrose pellet rewards in a two-lever choice task (one pellet vs. three pellets). Once rational choice behavior had been established, the probability of gaining three pellets was decreased over time (50%, 33%, 25% then 20%). The effect of D-amphetamine on decision making was studied at every probability level, as well as the effect of the dopamine D-1 receptor agonist SKF-81297 and D-2 agonist quinpirole at probability levels of 100% and 25%. D-Amphetamine increased unprofitable choices in a dose-dependent manner at the two lowest probability levels. Quinpirole increased the frequency of unprofitable decisions at the 25% probability level, and SKF-82197 did not affect choice behavior. These results mirror the findings of probabilistic discounting studies using food-restricted rats. Based on this, the use of AA rats provides a new approach for studies on reward-guided decision making. (C) 2017 Elsevier B.V. All rights reserved.Peer reviewe

Amphetamine primes enhanced motivation toward uncertain choices in rats with genetic alcohol preference

Comorbidity with gambling disorder (GD) and alcohol use disorder (AUD) is well documented. The purpose of our study was to examine the influence of genetic alcohol drinking tendency on reward-guided decision making behavior of rats and the impact of dopamine releaser D-amphetamine on this behavior. In this study, Alko alcohol (AA) and Wistar rats went through long periods of operant lever pressing training where the task was to choose the profitable of two options. The lever choices were guided by different-sized sucrose rewards (one or three pellets), and the probability of gaining the larger reward was slowly changed to a level where choosing the smaller reward would be the most profitable in the long run. After training, rats were injected (s.c.) with dopamine releaser D-amphetamine (0.3, 1.0 mg/kg) to study the impact of rapid dopamine release on this learned decision making behavior. Administration of D-amphetamine promoted unprofitable decision making of AA rats more robustly when compared to Wistar rats. At the same time, D-amphetamine reduced lever pressing responses. Interestingly, we found that this reduction in lever pressing was significantly greater in Wistar rats than in AA rats and it was not linked to motivation to consume sucrose. Our results indicate that conditioning to the lever pressing in uncertain environments is more pronounced in AA than in Wistar rats and indicate that the reinforcing effects of a gambling-like environment act as a stronger conditioning factor for rats that exhibit a genetic tendency for high alcohol drinking.Peer reviewe

The κ-opioid receptor antagonist JDTic decreases ethanol intake in alcohol-preferring AA rats

Studies suggest that the kappa-opioidergic system becomes overactivated as ethanol use disorders develop. Nalmefene, a currently approved treatment for ethanol use disorders, may also elicit some of its main effects via the kappa-opioidergic system. However, the exact role of kappa-opioid receptors on regulating ethanol intake and contribution to the development of ethanol addiction remains to be elucidated. The aim of the present study was to clarify the role of accumbal kappa-opioid receptors in controlling ethanol intake in alcohol-preferring Alko Alcohol (AA) rats. Microinfusions of the long-acting and selective kappa-opioid receptor antagonist JDTic (1-15 mu g/site) were administered bilaterally into the nucleus accumbens shell of AA rats voluntarily consuming 10% ethanol solution in the intermittent, time-restricted two-bottle choice access paradigm. JDTic (10 mg/kg) was also administered subcutaneously. Both the acute and long-term effects of the treatment on ethanol intake were examined. As a reference, nor-BNI (3 mu g/site) was administered intra-accumbally. Systemically administered JDTic decreased ethanol intake significantly 2 days and showed a similar trend 4 days after administration. Furthermore, intra-accumbally administered JDTic showed a weak decreasing effect on ethanol intake long-term but had no acute effects. Intra-accumbal administration of nor-BNI tended to decrease ethanol intake. The results provide further evidence that kappa-opioid receptors play a role in controlling ethanol intake and that accumbal kappa-opioid receptors participate in the modulation of the reinforcing effects of ethanol. Furthermore, the results suggest that kappa-opioid receptor antagonists may be a valuable adjunct in the pharmacotherapy of ethanol use disorders.Peer reviewe

The role of opioidergic system in modulating cost/benefit decision-making in alcohol-preferring AA rats and Wistar rats

Research has highlighted the association of a positive family history of alcoholism with a positive treatment response to opioid antagonists in those with a gambling disorder. However, the role of the opioidergic system in gambling behavior is not well understood, and preclinical studies are needed to clarify this. In this study, Alko Alcohol (AA) and Wistar rats went through operant lever pressing training where the task was to choose the more profitable of two options. Different sized sucrose rewards guided the lever choices, and the probability of gaining rewards changed slowly to a level where choosing the smaller reward was the most profitable option. After training, rats were administered subcutaneously with opioid agonist morphine or opioid antagonist naltrexone to study the impact of opioidergic mechanisms on cost/benefit decisions. No difference was found in the decision-making between AA rats or Wistar rats after the morphine administration, but control data revealed a minor decision enhancing effect in AA rats. Naltrexone had no impact on the decisions in AA rats but promoted unprofitable decisions in Wistar rats. Supporting behavioral data showed that in both rat strains morphine increased, and naltrexone decreased, sucrose consumption. Naltrexone also increased the time to accomplish the operant task. The results suggest that opioid agonists could improve decision-making in cost-benefit settings in rats that are naturally prone to high alcohol drinking. The naltrexone results are ambiguous but may partly explain why opioid antagonists lack a positive pharmacotherapeutic effect in some subgroups of gamblers.Peer reviewe

Ohjausvideo potilaalle eukapniseen voluntaariseen hyperventilaatiotestiin

Iho- ja allergiasairaalan kliinisen fysiologian yksikössä tehdään erilaisia keuhkojen toimintakokeita, joiden pääasiallinen käyttötarkoitus on astman diagnostiikka ja sen hoidon seuranta. Yksikkö on tuottanut potilasohjausvideoita heillä suoritettavista tutkimuksista Terveyskylän julkiseen verkkopalveluun, mutta eukapnisen voluntaarisen hyperventilaatiotestin osalta video vielä puuttui. Tutkimus on keskeinen astman diagnostiikassa käytettävistä ja keuhkoputkien supistumisherkkyyttä mittaavista tutkimuksista. Tämän toiminallisen opinnäytetyön aihe on ohjausvideo potilaalle eukapniseen voluntaariseen hyperventilaatiotestiin. Opinnäytetyön tarkoituksena oli tuottaa noin kolmen minuutin mittainen potilasohjausvideo kyseiseen tutkimukseen. Työn tavoitteena oli, että tuotoksena syntyvä ohjausvideo on hyödyksi tutkimukseen tulijalle sekä Iho- ja allergiasairaalan kliinisen fysiologian yksikön työntekijöille. Tietoperustan lähteiksi haettiin kotimaisia ja kansainvälisiä tieteellisiä julkaisuja ja tutkimuksia tietokannoista, kuten Pubmedista ja hakupalveluista, kuten Google Scholarista. Kansainvälisiä e-aineistoja on haettu myös Metropolian kirjaston verkkopalvelun MetCat Finnan kautta. Tietoperustaan kerättiin monipuolisesti tietoa astman diagnostiikasta ja hoidon seurannasta, keuhkoputkien epäsuorista altistusmenetelmistä, eukapnisesta voluntaarisesta hyperventilaatiotestistä, potilasohjauksesta ja ohjausvideon teosta. Opinnäytetyön tuotoksena valmistui 3 minuutin ja 6 sekunnin pituinen ohjausvideo, ohjausvideon käsikirjoitus, palautekysely sekä opinnäytetyön raportti. Opinnäytetyön oheistuotteena valmistui myös Iho- ja allergiasairaalan kliinisen fysiologian yksikön henkilökunnalle tarkoitettu perehdytysvideo eukapniseen voluntaariseen hyperventilaatiotestiin. Opinnäytetyö toteutettiin yhteistyössä Metropolia ammattikorkeakoulun ja Iho- ja allergiasairaalan välillä

The selective κ-opioid receptor antagonist JDTic attenuates the alcohol deprivation effect in rats

The mechanisms behind relapse to ethanol intake in recovering alcoholics are still unclear. The negative reinforcing effects contributing to ethanol addiction, including relapse, are considered to be partly driven by the kappa-opioidergic system. As the kappa-opioidergic system interacts with the mesolimbic reward pathway, the aim of the study was to clarify the role of nucleus accumbens shell kappa-opioidergic mechanisms in relapse to ethanol intake by using the alcohol deprivation effect (ADE) paradigm. The ADE is defined as a transient increase in voluntary ethanol intake after a forced period of abstinence. Male Long-Evans rats were trained to voluntarily consume 10% (v/v) ethanol solution. Ethanol access and deprivation cycles were initiated after stable ethanol intake baselines had been reached and bilateral guide cannulas had been implanted above the nucleus accumbens shell. One cycle consisted of 10 days of 90 min access to ethanol followed by 6 days of ethanol deprivation. The ADE was measured in the beginning of a new cycle. Rats received JDTic, a selective kappa-antagonist, either subcutaneously (10 mg/kg) or intra-accumbally (15 mu g/site) or, as a reference substance, systemic naltrexone (0.3 mg/kg) before ethanol re-access, and the effects on the ADE were evaluated. Systemic and intra-accumbal JDTic significantly attenuated the ADE on the first day of ethanol re-access, as did systemic naltrexone. Additionally, naltrexone decreased ethanol intake levels. These results suggest that nucleus accumbens shell kappa-opioidergic mechanisms may have a role in mediating relapse to ethanol intake. Additionally, kappa-antagonism could be a valuable adjunct in ethanol relapse prevention. (C) 2019 Elsevier B.V. and ECNP. All rights reserved.Peer reviewe