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Alcohol abuse

Study: Susceptibility to alcohol abuse in bypass patients

Reward-related and neuroendocrine mechanisms are likely involved in RYGB-related increase in alcohol reward

Roux-en-Y gastric bypass (RYGB) patients have an increased susceptibility to alcohol abuse, and the procedure-related increase in alcohol reward involves neuroendocrine mechanisms, according to a study published online at PlosOne.

The study researchers from Pennsylvania State University College of Medicine, the National Institute on Alcohol Abuse and Alcoholism, the National Institute on Drug Abuse, Brown University and Stony Brook University, said that additional research is required to see whether these preliminary findings could be translated to humans and confirm the underlying mechanisms, which might result in personalised interventions and treatments.

The authors write that recent studies reported increased risk for ethanol (EtOH) consumption following RYGB, and has heightened concerns as to whether the procedure increases the vulnerability for alcohol use disorder.

They state that studies have shown RYGB patients have higher and longer-lasting blood EtOH concentrations, and a shorter period of onset than non-surgical controls when consuming similar amounts of EtOH.

These changes in EtOH’s absorption and pharmacokinetics may alter not only the bioavailability and stimulating properties of EtOH on the brain, but also influence the neuronal and hormonal signals upstream of the reward system.

“However, the extent of which RYGB contributes to the increase in alcohol reward independent of the changes in EtOH absorption and pharmacokinetics is unclear,” they note.

As previous studies have looked at the effects of orally-administered orally EtOH, it has not been possible to differentiate if the effects were due to a direct enhancement of EtOH’s rewarding effects, or to an indirect effect brought about by changes in EtOH’s absorption and consequent bioavailability and pharmacokinetics.

Study

Therefore, for this study the investigators used an intravenous (IV) operant model of EtOH self-administration to evaluate direct changes in alcohol reward without the potential confound of changes in EtOH’s absorption.

They hypothesised that “RYGB would increase EtOH’s rewarding effects (even when administered IV), thus increasing overall EtOH self-administration and animals’ willingness to seek and work for EtOH.”

Twelve adult (four week old) male Sprague Dawley with starting weights between 250–275g  received a nutritionally complete high fat diet for at least 26 weeks prior to and throughout the study.

After 26–28 weeks on a high fat diet, animals received either RYGB or SHAM. Three days after the procedure, the animals returned to their high fat diet.

Approximately two months the rats were connected to a computer controlled IV infusion of EtOH (1%).

After surgical recovery, rats were overnight water deprived for continuous access training. For two days, rats received 1 hr water access in the operant chambers and 3 hrs of water access each afternoon in their home cages to ensure proper hydration. Following two days of water training, rats began daily EtOH self-administration sessions of one hr duration.

Rats were placed in the operant chambers with three spouts: spout 1 (left – “water” spout), spout 2 (middle – “active” spout) and spout 3 (right – “inactive” spout) were empty. Upon program activation, empty spouts 2 and 3 were presented, with licks on the inactive spout producing no programmed consequences and licks on the active spout counting towards completion of the FR5 schedule of reinforcement.

Following 12 days of FR5 acquisition and maintenance, the schedule was changed to a PR2 requirement, where requirement for EtOH access increased by 2 licks per reinforcement (PR2: i.e. 2, 4, 6, etc.). If subjects did not meet the scheduled requirement after 10 minutes, the session was terminated without a reinforcement reward, providing the animals’ breakpoint (defined as the number of reinforcement cycles completed). Assuming the subject reached the active spout requirement, the water spout was presented for a 10s interval, during which licks were recorded. At the end of the 10s interval, the spout retracted and the procedure was repeated.

Results

Preoperative body mass for RYGB and SHAM was 636.84±61.30g, and 611.42±11.1 g, respectively (NS). At the beginning of the EtOH self-administration, RYGB rats weighed 594.3±43.0g, while SHAM rats weighed 734.7±32.7g.  During the experiment, body weight was significantly lower in RYGB rats.

RYGB rats made significantly more EtOH infusions and more licks in the active spout than SHAM rats (Figure 1).

Figure 1. RYGB rats (n=6) worked harder for, and infused more IV ethanol during FR self-administration sessions than SHAM controls (n=6).

The number of infusions earned by RYGB and SHAM rats differed (Figure 2a), post hoc analysis revealed that RYGB rats earned significantly more infusions on the second day of PR testing than SHAM rats (p<0.05).

Figure 2. RYGB rats (n=6) worked harder for, and infused more IV ethanol during PR self-administration sessions than SHAM controls (n=6).

“Obese rats after RYGB self-administered more EtOH and had higher breakpoints than SHAM obese control,” the authors note. “Since the EtOH was administered IV, this provides evidence that the rewarding effects of EtOH were not due to increased absorption following RYGB.”

The results revealed that the RYGB rats displayed a significant increase in EtOH-seeking behaviours, compared to SHAM controls, but RYGB rats also expended more efforts to earn EtOH reward and displayed increased EtOH consumptions even on days when differences did not reach statistical significance.

“Our current findings not only are consistent with previous ones investigating the effects of RYGB on oral EtOH intake, but also represent the first demonstration of the effects of RYGB on IV EtOH administration…it is likely that RYGB alters the sensitivity to alcohol reward, presumably through effects in the mesolimbic dopamine system.”

“Additionally, our findings most likely reflect post-RYGB metabolic and endocrine changes that impact the sensitivity of the brain to alcohol reward. In fact, modest changes in ghrelin sensitivity may exert behaviourally relevant effects, and might be a contributing factor in increased alcohol reward following RYGB.”

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