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.

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 κ-opioidergic system. As the κ-opioidergic system interacts with the mesolimbic reward pathway, the aim of the study was to clarify the role of nucleus accumbens shell κ-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 κ-antagonist, either subcutaneously (10 mg/kg) or intra-accumbally (15 µg/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 κ-opioidergic mechanisms may have a role in mediating relapse to ethanol intake. Additionally, κ-antagonism could be a valuable adjunct in ethanol relapse prevention.

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

RATIONALE: Studies suggest that the κ-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 κ-opioidergic system. However, the exact role of κ-opioid receptors on regulating ethanol intake and contribution to the development of ethanol addiction remains to be elucidated. OBJECTIVES: The aim of the present study was to clarify the role of accumbal κ-opioid receptors in controlling ethanol intake in alcohol-preferring Alko Alcohol (AA) rats. METHODS: Microinfusions of the long-acting and selective κ-opioid receptor antagonist JDTic (1-15 µg/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 µg/site) was administered intra-accumbally. RESULTS: 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. CONCLUSIONS: The results provide further evidence that κ-opioid receptors play a role in controlling ethanol intake and that accumbal κ-opioid receptors participate in the modulation of the reinforcing effects of ethanol. Furthermore, the results suggest that κ-opioid receptor antagonists may be a valuable adjunct in the pharmacotherapy of ethanol use disorders.

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

RATIONALE: Comorbidity with gambling disorder (GD) and alcohol use disorder (AUD) is well documented. OBJECTIVE: 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. METHODS: 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. RESULTS: 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. CONCLUSIONS: 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.

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 D1 receptor agonist SKF-81297 and D2 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.

Accumbal µ-Opioid Receptors Modulate Ethanol Intake in Alcohol-Preferring Alko Alcohol Rats.

BACKGROUND: The nucleus accumbens shell is a key brain area mediating the reinforcing effects of ethanol (EtOH). Previously, it has been shown that the density of µ-opioid receptors in the nucleus accumbens shell is higher in alcohol-preferring Alko Alcohol (AA) rats than in alcohol-avoiding Alko Non-Alcohol rats. In addition, EtOH releases opioid peptides in the nucleus accumbens and opioid receptor antagonists are able to modify EtOH intake, all suggesting an opioidergic mechanism in the control of EtOH consumption. As the exact mechanisms of opioidergic involvement remains to be elucidated, the aim of this study was to clarify the role of accumbal µ- and κ-opioid receptors in controlling EtOH intake in alcohol-preferring AA rats. METHODS: Microinfusions of the µ-opioid receptor antagonist CTOP (0.3 and 1 µg/site), µ-opioid receptor agonist DAMGO (0.03 and 0.1 µg/site), nonselective opioid receptor agonist morphine (30 µg/site), and κ-opioid receptor agonist U50488H (0.3 and 1 µg/site) were administered via bilateral guide cannulas into the nucleus accumbens shell of AA rats that voluntarily consumed 10% EtOH solution in an intermittent, time-restricted (90-minute) 2-bottle choice access paradigm. RESULTS: CTOP (1 µg/site) significantly increased EtOH intake. Conversely, DAMGO resulted in a decreasing trend in EtOH intake. Neither morphine nor U50488H had any effect on EtOH intake in the used paradigm. CONCLUSIONS: The results provide further evidence for the role of accumbens shell µ-opioid receptors but not κ-opioid receptors in mediating reinforcing effects of EtOH and in regulating EtOH consumption. The results also provide support for views suggesting that the nucleus accumbens shell has a major role in mediating EtOH reward.