RYGB rats drank significantly more EtOH (low and high dose) during habituation and reinstatement relative to Sham-HF animals and also drank significantly more EtOH (low dose) during habituation than Naïve-ND rats. Specifically, during habituation RYGB rats had 300–400% greater daily EtOH intake than Sham-HF rats and 50–100% greater ethanol intake than Naïve-ND. This effect remained apparent after normalizing for body weight ().
EtOH intake in RYGB rats when compared with Sham-HF rats was significantly higher throughout the 2%, 4%, 6% and 8% EtOH habituation, and during the 8% reinstatement. In contrast, EtOH intake in RYGB rats when compared with Naïve-ND rats was only significantly higher for the low EtOH concentrations (2 and 4%) and only during the habituation phase (; ). Sham-HF rats showed the lowest EtOH intake both when compared to RYGB and Naïve-ND suggesting a protective effect of obesity vis-a-vis EtOH consumption. The fact that there were no differences in EtOH intake between RYGB and Naïve-ND during reinstatement () suggests that RYGB may remove the protective effect that obesity has on alcohol intake. Note that here we excluded a protective effect of HF diet on alcohol intake since both the obese control (Sham-HF) and the RGYB rats were exposed to HF diets. Moreover studies on the effects of HF diets on EtOH intake have shown either increased intake [18
] or varying effects [19
] but no evidence of reductions in EtOH intake.
Here we also showed that RYGB rats consumed significantly more food and total calories (food + alcohol) than obese or lean controls (). This differs from prior findings on RYGB rats that showed markedly decreased caloric intake [20
]. These discrepancies may reflect the fact that we exposed RYGB to HF diets whereas prior studies exposed obesity-prone animal strains to normal chow diets [21
]. The consistency of the high fat diet differs from that of chow in that it is softer and contains more liquid allowing RYGB rats to consume larger volumes that from chow food. Also we calculated food intake as the difference between the weight of the food placed in the cage and the weight of the food removed on the following day. However this is not a precise measure since rats will frequently gnaw on food and significant amounts drop through the open bottom cage. It is also possible that the longer period elapsed from surgery in our study (26 weeks) than in prior ones (3–15 weeks) allowed the gastrointestinal systems of our RYGB animals to adapt allowing them to feed more frequently [21
]. In fact 20% of patients have been reported to regain and have ‘food urges’ about one year after their RYGB procedure [22
Excessive malabsorption of vitamins and micronutrients occurs with RYGB procedures, which also severely hinder the absorption of dietary fat [24
]. Thus the excessive food consumption in the RYGB rats may have reflected an attempt to compensate for their decreased absorption of fat and other nutrients. Fecal fat analysis may be used in the future to test this hypothesis.
It has to be noted that anatomic reasons (i.e. the rat stomach contains a thin walled rumen which cannot be surgically divided), the operation in rats is not as restrictive as in humans and the pouch-size greatly varies across laboratories (for a review, see [25
]). Furthermore, RYGB procedures differ by surgeon, and in our study a 30 cm portion of the bilio-pancreatic limb was bypassed as opposed to 10–16 cm portion used in studies reporting less food intake [20
]. Greater limb bypass means less nutrient absorption, which may contribute to an increased drive for food intake due to the likely decrease in nutrient absorption. Stylopoulous and Xu both report weight stabilization after the initial weight loss from the RYGB procedure, which suggests in our model as well as theirs, that the experimental animals maintain weight homeostasis through caloric consumption.
It is interesting to note that for the RYGB rats only, food intake was positively associated with increases in total fluid intake, which suggests that their total fluid intake may be driven in part by the increased food consumption requiring the associated intake of fluids. However, the correlation was not significant when assessed for water or EtOH alone, which may reflect the fact that the relevant variable may have been total liquid intake. Ethanol intake was not significantly correlated with water intake for the RYGB or HF groups.
The highest EtOH intake in the RYGB animals was seen for the low concentrations (2 and 4%) (), which could reflect enhanced sensitivity to the rewarding effects of low EtOH concentrations. This could reflect the faster absorption of EtOH [12
], the reduced metabolism [26
] of EtOH following RYGB surgery and/or the lower body weight and hence greater brain bioavailability of EtOH [20
The RYGB rats also consumed more 8% EtOH during reinstatement relative to Sham-HF rats, but did not differ from Naive-ND rats. We did not observe a rebound in EtOH intake following 2-week EtOH deprivation in any of the groups, which differs from other reports [16
]. The reasons for these differences are unclear and may reflect differences in doses and regimes of EtOH exposures. Also the short time period used for habituation may have precluded us from observing a rebound [16
Interestingly, RYGB animals did not differ on their preference of EtOH over water from the other groups) and their water intake was also significantly higher than that of the other groups when exposed to high EtOH concentrations (6 and 8%) or when not given ethanol (, ). RYGB rats demonstrated a 66% increase in water intake compared to Naïve-ND rats and up to a 100% increase compared to Sham-HF rats. The generalized increase of total fluid consumption (EtOH and water) explains why preference measured by EtOH over total fluid intake did not differ between RYGB and the other cohorts.
The increased EtOH consumption in the RYGB rats over the Sham-HF rats could reflect differences in EtOH metabolism, bioavailability and/or changes in alcohol’s pharmacokinetics [12
]. Alcohol metabolism is disrupted after RYGB surgery and the disruption increases with the time passed following the procedure [26
]. In contrast, the absorption of ethanol increases drastically, leading to an increased sensitivity [12
], which could explain the drop-off of ethanol intake in the RYGB group at the 6% and 8% EtOH concentrations, and the high levels of drinking at 2% and 4%. Thus the combination of high sensitivity to low dose ethanol with increased drinking of all solutions (water and EtOH) could explain why the RYGB animals did not show a preference for EtOH over water even when they were consuming markedly more than the control groups.
Ethanol consumption could also reflect metabolic changes triggered by the surgery. For example, increased sensitivity to ghrelin following surgery may have contributed, since ghrelin increases ethanol consumption and ghrelin antagonists block the rewarding effects of alcohol in rodents [27
]. Resistance to ghrelin in diet induced obese rodents [28
] could explain the lower alcohol consumption in the Sham-HF animals. As of now the findings on the effects of bariatric surgery in ghrelin concentration have been inconsistent; one study showed decreases [29
], others showed no changes and one showed increases [30
]; and to our knowledge there are no reported studies on the effects of bariatric surgery on ghrelin sensitivity. Similarly changes in leptin concentration and sensitivity following RYGB [31
] may have contributed since leptin also modulates reward centers of the brain [32
]. However since we did not measure ghrelin nor leptin we can not test this hypothesis.
Ethanol consumption occurs both for its nutrient (calories) and pharmacological effects (increasing dopamine and endogenous opiates among others) [16
]. The fact that RYGB rats also showed increased food consumption suggests that the enhanced EtOH intake may be influenced in part by EtOH’s caloric content. Interestingly gastric bypass in humans has been shown to increase the expression of dopamine D2 receptors in the ventral striatum and caudate nucleus by one study [5
] though another study showed the opposite effect [6
]. This is significant since the ventral striatum is involved with alcohol’s pharmacological effects [33
]. Thus changes in brain dopamine neurotransmission following gastric bypass could also contribute to enhanced ethanol intake. The caloric effect of a 2% or 4% solution (the EtOH concentrations at which the RYGB group was shown to have increased consumption) is minor compared to the caloric intake from high fat food, but our study suggests that these solutions may be consumed more by RYGB subjects, presumably due to enhanced ethanol absorption [12
]; hindered metabolism [26
] following a RYGB and a negative energy balance relative to the control groups.
In summary, here we show that gastric bypass surgery significantly increased alcohol consumption of low EtOH concentrations and increased water intake (at high EtOH concentrations), which provides some support for the clinical reports that bariatric surgery is associated with an increased risk for alcohol abuse. We also document a protective effect of HF-induced obesity on alcohol intake. Though we postulate that metabolic adaptations with obesity (ie ghrelin and leptin resistance) may underlie the protective effects of obesity toward consumption of large quantities of EtOH and their reversal following surgery may underlie the risk for alcohol abuse, further studies are needed to test this and other metabolic factors that could affect caloric and fluid intakes.