Feasibility Study of Bariatric Surgery in a Rat Model of Spinal Cord Injury to Achieve Beneficial Body Weight Outcome.

Approximately two thirds of spinal cord injury (SCI) persons become overweight or obese. Obesity increases the risk of developing type 2 diabetes and limits self-help techniques. Weight-loss surgery (WLS), including vertical sleeve gastrectomy (VSG), is regarded as highly effective in the long-term treatment of obesity and remission of associated type 2 diabetes. Given the increased risk of obesity post-SCI, WLS offers an attractive intervention strategy. Alterations in the physiology of energy homeostasis after SCI necessitate that SCI persons should not be regarded as similar to able-bodied persons. Because of current knowledge gaps, it is unknown whether an obese phenotype with SCI will respond to WLS similarly to the neurally intact obese phenotype. Therefore, this study tested the hypothesis that the VSG procedure is well tolerated and effective in an animal model of high-thoracic (T3) SCI. In Wistar male rats, subsequent to a 2-week recovery period after T3-SCI, but not control laminectomy surgery, daily consumption of a high-fat diet (HFD; 60% kcal from fat) was elevated over 4 weeks preceding VSG. After a 2-week recovery period post-VSG, HFD consumption in T3-SCI rats over a 4-week monitoring period returned to levels comparable to control. Body weight was significantly reduced in T3-SCI rats and remained reduced whereas control rats regained body weight. Further, no adverse complications directly attributable to the VSG procedure were identified. Thus, this rodent model is a viable tool for addressing fundamental questions regarding the mechanisms leading to obesity post-SCI and the development of translational strategies.

Changes in plasma ghrelin levels following surgical and non-surgical weight-loss in female rats predict alcohol use.

The weight-loss surgery Roux-en Y gastric bypass (RYGB) is a relatively effective, long-term treatment option for patients with morbid obesity. However, accumulating clinical evidence suggests that patients receiving RYGB may be at increased risk of developing alcohol use disorder. This observation has been repeatedly supported by preclinical studies showing rodents increase intake of ethanol (EtOH) after RYGB, and has been further confirmed by human studies. A promising alternative to RYGB is sleeve gastrectomy (SG), which has resulted in decreased EtOH consumption in some rodent studies. The exact mechanism underlying the differential alcohol outcomes after RYGB versus SG has yet to be elucidated. However, the gut hormone ghrelin has emerged as a potential candidate from previous preclinical studies specific to RYGB surgeries and due to its action to stimulate food and alcohol intake and cravings. To directly assess changes in plasma ghrelin levels following weigh loss surgeries in the context of alcohol intake, 24 female rats were separated into three surgical groups receiving RYGB, SG, or Sham surgery followed by caloric restriction to produce adiposity matched controls (Sham-AM). Blood was drawn for fasted and fed plasma ghrelin (acyl and des-acyl) assays at multiple time points: while on a normal diet (ND), after 5-week exposure to a high fat diet (HFD), following surgery, and after a series of two-bottle alcohol choice test with increasing concentrations (2%, 4%, 6%, 8%) of EtOH. Consistent with previous observations, RYGB rats drank more EtOH than SG rats across all concentrations. As expected, fasted ghrelin levels were blunted after HFD feeding, compared to normal diet baseline. After RYGB, fasted ghrelin levels returned to higher levels while remained blunted after SG and Sham-AM. Fed acyl ghrelin levels were significantly increased to above "normal" levels after RYGB, but remain low after SG and Sham-AM. Given that post-RYGB acyl ghrelin levels are raised to a fasted state regardless of actual prandial status, we conclude that RYGB may results in a hormonal state reminiscence of a fasted state with the inability of feeding to inhibit ghrelin production, an effect which could potentially contribute to increased EtOH intake following the surgery. In contrast, following SG, ghrelin levels in rats remain consistent with the fed state regardless of prandial status, potentially explaining lower alcohol intake and lower risk of developing AUD.

Glucagon-like peptide-1 receptor agonist, liraglutide, reduces heroin self-administration and drug-induced reinstatement of heroin-seeking behaviour in rats.

Drug addiction is a chronic brain disease characterized by the uncontrolled use of a substance. Due to its relapsing nature, addiction is difficult to treat, as individuals can relapse following even long periods of abstinence and, it is during this time, that they are most vulnerable to overdose. In America, opioid overdose has been increasing for decades, making finding new treatments to help patients remain abstinent and prevent overdose deaths imperative. Recently, glucagon-like peptide-1 (GLP-1) receptor agonists have shown promise in reducing motivated behaviours for drugs of abuse. In this study, we test the effectiveness of the GLP-1 analogue, liraglutide (LIR), in reducing heroin addiction-like behaviour, and the potential side effects associated with the treatment. We show that daily treatment with LIR (0.1 mg/kg sc) increases the latency to take heroin, reduces heroin self-administration, prevents escalation of heroin self-administration and reduces drug-induced reinstatement of heroin-seeking behaviour in rats. A 1-h pretreatment time, however, was too short to reduce cue-induced seeking in our study. Moreover, we showed that, while LIR (0.1, 0.3, 0.6 and 1.0 mg/kg sc) supported conditioned taste avoidance of a LIR-paired saccharin cue, it did not elicit intake of the antiemetic kaolin in heroin-naïve or heroin-experienced rats. Further, 0.1 mg/kg LIR did not produce great disruptions in food intake or body weight. Overall, the data show that LIR is effective in reducing heroin taking and heroin seeking at doses that do not cause malaise and have a modest effect on food intake and body weight gain.

Differential Response in Ethanol Behaviors of Female Rats Given Various Weight Loss Surgeries.

AIMS: Currently, the only effective treatment for morbid obesity and its comorbidities is weight loss surgery (WLS). Growing evidence suggests that different types of WLS, such as Roux-en-Y gastric bypass (RYGB) and sleeve gastrectomy (SG), have differential effects on alcohol consumption in humans and rats. Thus, we aimed to directly compare the effects of these two surgical procedures, for the first time in female rats, and to determine whether presence or absence of the ghrelin-producing stomach tissue has critical influence on postoperative alcohol intake. METHODS: We performed two experiments using an identical behavioral protocol, a continuous-access two-bottle choice protocol for various concentrations of ethanol (EtOH). In Experiment 1, 23 high fat diet (HFD) obese, female rats were randomized to three groups: RYGB, SG or sham-operated food-restricted (Sham) controls. In Experiment 2, HFD obese female rats received either sham (n = 11) or a modified RYGB surgery where the remnant stomach was removed (RYGB-X; n = 12). RESULTS: SG rats drank significantly less than RYGB for 4, 6 and 8% and significantly less than Sham for 6, 8 and 8% reinstatement. RYGB-X consumed significantly less EtOH than Sham across all concentrations, reaching significance for 6 and 8% reinstatement. CONCLUSION: These findings confirm reduced EtOH consumption by female SG rats as opposed to increased intake following RYGB, and provide the first experimental evidence that the remnant stomach in the RYGB procedure is contributory. Future studies in rats and humans are warranted to confirm that ghrelin plays a critical role in susceptibility to AUD development following WLS.

Vagotomy increases alcohol intake in female rats in diet dependent manner: Implications for increased alcohol use disorder after roux-en-y gastric bypass surgery.

A variety of weight loss surgeries have been developed to fight the obesity epidemic, with Roux-en-Y gastric bypass (RYGB) being one of the most effective and popular procedures. However, the underlying mechanisms behind its efficacy are still not well understood. Furthermore, growing clinical evidence suggests that RYGB may result in increased risk for development of alcohol use disorder (AUD). The vagus nerve is a potentially critical contributor to increased risk of AUD following RYGB due to the potential for significant damage to the vagus during surgery, which has been confirmed in rodent studies. Studies aiming at the mechanisms underlying development of alcohol or substance use disorders following the surgery have exclusively used male rats, despite the majority of RYGB patients being female. Thus, the current study had two objectives: 1) to investigate the effect of RYGB on ethanol (EtOH) intake in female rats using a protocol previously established in male rats, and 2) to test the effect of vagal damage and high fat diet (HFD) on EtOH intake in female rats. In the first study, 22 female rats were maintained on HFD for four weeks and then split into two surgical groups, RYGB (n = 10) and Sham (n = 12). All rats then underwent a two-bottle choice test of increasing EtOH concentrations: 2%, 4%, 6%, 8%. Rats were then forced to abstain from EtOH for two weeks, after which access to 8% EtOH was reinstated. The RYGB female rats significantly increased their intake for low concentrations of EtOH (2% and 4%) and during the reinstatement period for 8%. These results mirror those seen in male rats, and thus, confirms RYGB in female rats as an equally viable model to males. In the second study, 40 female rats were separated into four groups: HFD/Sham, HFD/Vagotomy, normal diet (ND)/Sham, and ND/Vagotomy. All rats then were subjected to the same two-bottle choice test protocol as in the previous study. Rats in the vagotomy condition had significantly greater preference for 2% and 4% EtOH compared with Sham-operated controls. EtOH intake, either in ml or adjusted for body weight, was greater in rats maintained on ND compared with rats maintained on HFD. These data suggest that vagal damage may, at least in part, contribute to increased preference for EtOH. Furthermore, this increase in EtOH preference is counter to the blunting effect of HFD. In conclusion, the data presented here suggest a role for vagal damage in risk of AUD after weight loss surgery.

Effect of vertical sleeve gastrectomy on alcohol consumption and preferences in dietary obese rats and mice: A plausible role for altered ghrelin signaling.

Vertical sleeve gastrectomy (VSG) and Roux-en-Y gastric bypass (RYGB) are the most common surgical options for the treatment of obesity and metabolic disorder. Whereas RYGB may result in greater and more durable weight loss, recent clinical and pre-clinical studies in rats have raised concerns that RYGB surgery may increase risk for alcohol use disorder (AUD). In contrast, recent clinical reports suggest a lesser risk for AUD following VSG, although no preclinical studies have been done to confirm that. Therefore, the present study sought to determine the effects of VSG on ethanol intake and preferences in rodent models using protocols similar to those previously used in animal studies for RYGB. Male Sprague Dawley rats and male C57B6 mice were made obese on a high fat diet (60%kcal from fat) and received VSG or no surgery (controls). All animals then were given access to increasing concentrations of ethanol (2%, 4%, 6%, and 8%), presented for few days each. Compared to controls, VSG rats consumed significantly less of 2, 6 and 8% ethanol and showed significantly reduced preferences to 6 and 8% ethanol over water. VSG mice also displayed reduced intake and preference for 6 and 8% ethanol solutions. After a two-week period of forced abstinence, 8% ethanol was reintroduced and the VSG rats and mice continued to exhibit reduced consumption and less preference for ethanol. Regarding the underlying mechanism, we hypothesized that the removal of the ghrelin producing part of the stomach in the VSG surgery is a possible contributor to the observed reduced ethanol preference. To test for functional changes at the ghrelin receptors, the VSG and control rats were given IP injections of acyl-ghrelin (2.5nmol and 5nmol) prior to ethanol access. Neither concentration of ghrelin resulted in a significant increase in 8% ethanol consumption of VSG or control subjects. Next, the rats were given IP injections of the ghrelin receptor antagonist, JMV (2.5mg/kg body weight). This dose induced a significant reduction in 8% ethanol consumption in the VSG group, but no effect on ethanol intake in the controls. While ghrelin injection was uninformative, increased sensitivity to subthreshold doses of the ghrelin receptor antagonist may indicate reduced ghrelin signaling following VSG. Overall, these findings suggest that bariatric patients with increased susceptibility to AUD may benefit from receiving VSG instead of RYGB surgery, and that changes in ghrelin signaling, at least in part, may play a role in the differential AUD risks between the two most commonly performed bariatric surgical procedures.

Increased intravenous morphine self-administration following Roux-en-Y gastric bypass in dietary obese rats.

Roux-en-Y gastric bypass (RYGB) surgery is a commonly performed and very effective method to achieve significant, long-term weight loss. Opioid analgesics are primarily used to manage postoperative pain as fewer alternative medication options are available for bariatric surgery patients than for the general population. Recent clinical studies support a greater risk for substance use following bariatric surgery, including an increased use of opioid medications. The present study is the first to study morphine self-administration in a rat model of RYGB. High fat diet-induced obese (HFD-DIO) rats underwent RYGB (n=14) or sham-surgery with ad libitum HFD (SHAM, n=14) or a restricted amount that resulted in weight matched to the RYGB cohort (SHAM-WM, n=8). An additional normal-diet (ND, n=7), intact (no surgery) group of rats was included. Two months after the surgeries, rats were fitted with jugular catheters and trained on a fixed ratio-2 lick task to obtain morphine intravenously. Both morphine-seeking (number of licks on an empty spout to obtain morphine infusion) and consumption (number of infusion) were significantly greater in RYGB than any control group beginning on day 3 and reached a two-fold increase over a period of two weeks. These findings demonstrate that RYGB increases motivation for taking morphine and that this effect is independent of weight loss. Further research is warranted to reveal the underlying mechanisms and to determine whether increased morphine use represents a risk for opioid addiction following RYGB. Identifying risk factors preoperatively could help with personalized postoperative care to prevent opioid abuse and addiction.

Furosemide, sodium appetite, and ingestive behavior.

Sodium appetite is often produced experimentally by using the diuretic furosemide (Furo) to induce a rapid loss of urinary sodium. The present experiments were designed to investigate the dose-dependent relationship between renal and behavioral responses to Furo. We compared the effects of five different Furo doses (0.5, 1, 2, 6, and 10 mg) on 3% NaCl intake, water intake, Na(+)-free chow intake, urine quantity, electrolyte balance, and weight gain in rats. The Na(+) loss produced by Furo injection was dose dependent from 0.5 to 10 mg and did not change across repeated depletions. There was only a weak correspondence, however, between these dose-dependent changes in renal function and subsequent sodium appetite. This suggests that net Na(+) loss is not the only determinant of sodium intake. Moreover, at the two higher doses of Furo, both food intake and weight dropped significantly, but these did not change following the three lower ones. Given these substantial side effects, the preferred dose of Furo for inducing a salt appetite should not exceed 2.0 mg.