Changes in Alcohol Use after Metabolic and Bariatric Surgery: Predictors and Mechanisms.

PURPOSE OF REVIEW: This review synthesized the literature on predictors and mechanisms of post-bariatric alcohol problems, in order to guide future research on prevention and treatment targets. RECENT FINDINGS: Consistent evidence suggests an elevated risk of developing problems with alcohol following bariatric surgery. While there is a paucity of empirical data on predictors of problematic alcohol use after bariatric surgery, being male, a younger age, smoking, regular alcohol consumption, pre-surgical alcohol use disorder, and a lower sense of belonging have predicted alcohol misuse post-operatively. This review synthesizes potential mechanisms including specific bariatric surgical procedures, peptides and reinforcement/reward pathways, pharmacokinetics, and genetic influences. Finally, potential misperceptions regarding mechanisms are explored. Certain bariatric procedures elevate the risk of alcohol misuse post-operatively. Future research should serve to elucidate the complexities of reward signaling, genetically mediated mechanisms, and pharmacokinetics in relation to alcohol use across gender and developmental period by surgery type.

Energy homeostasis in apolipoprotein AIV and cholecystokinin-deficient mice.

Apolipoprotein AIV (ApoAIV) and cholecystokinin (CCK) are well-known satiating signals that are stimulated by fat consumption. Peripheral ApoAIV and CCK interact to prolong satiating signals. In the present study, we hypothesized that ApoAIV and CCK control energy homeostasis in response to high-fat diet feeding. To test this hypothesis, energy homeostasis in ApoAIV and CCK double knockout (ApoAIV/CCK-KO), ApoAIV knockout (ApoAIV-KO), and CCK knockout (CCK-KO) mice were monitored. When animals were maintained on a low-fat diet, ApoAIV/CCK-KO, ApoAIV-KO, and CCK-KO mice had comparable energy intake and expenditure, body weight, fat mass, fat absorption, and plasma parameters relative to the controls. In contrast, these KO mice exhibited impaired lipid transport to epididymal fat pads in response to intraduodenal infusion of dietary lipids. Furthermore, ApoAIV-KO mice had upregulated levels of CCK receptor 2 (CCK2R) in the small intestine while ApoAIV/CCK-KO mice had upregulated levels of CCK2R in the brown adipose tissue. After 20 wk of a high-fat diet, ApoAIV-KO and CCK-KO mice had comparable body weight and fat mass, as well as lower energy expenditure at some time points. However, ApoAIV/CCK-KO mice exhibited reduced body weight and adiposity relative to wild-type mice, despite having normal food intake. Furthermore, ApoAIV/CCK-KO mice displayed normal fat absorption and locomotor activity, as well as enhanced energy expenditure. These observations suggest that mice lacking ApoAIV and CCK have reduced body weight and adiposity, possibly due to impaired lipid transport and elevated energy expenditure.

Behavioral and physiological consequences of enrichment loss in rats.

Significant loss produces the highest degree of stress and compromised well-being in humans. Current rodent models of stress involve the application of physically or psychologically aversive stimuli, but do not address the concept of loss. We developed a rodent model for significant loss, involving removal of long-term access to a rewarding enriched environment. Our results indicate that removal from environmental enrichment produces a profound behavioral and physiological phenotype with depression-like qualities, including helplessness behavior, hypothalamo-pituitary-adrenocortical axis dysregulation and overeating. Importantly, this enrichment removal phenotype was prevented by antidepressant treatment. Furthermore, the effects of enrichment removal do not occur following relief from chronic stress and are not duplicated by loss of exercise or social contact.

Central & peripheral glucagon-like peptide-1 receptor signaling differentially regulate addictive behaviors.

Recent data implicate glucagon-like peptide-1 (GLP-1), a potent anorexigenic peptide released in response to nutrient intake, as a regulator for the reinforcing properties of food, alcohol and psychostimulants. While, both central and peripheral mechanisms mediate effects of GLP-1R signaling on food intake, the extent to which central or peripheral GLP-1R signaling regulates reinforcing properties of drugs of abuse is unknown. Here, we examined amphetamine reinforcement, alcohol intake and hedonic feeding following peripheral administration of EX-4 (a GLP-1 analog) in FLOX and GLP-1R KD(Nestin) (GLP-1R selectively ablated from the central nervous system) mice (n=13/group). First, the effect of EX-4 pretreatment on the expression of amphetamine-induced conditioned place preference (Amp-CPP) was examined in the FLOX and GLP-1R KD(Nestin) mice. Next, alcohol intake (10% v/v) was evaluated in FLOX and GLP-1R KD(Nestin) mice following saline or EX-4 injections. Finally, we assessed the effects of EX-4 pretreatment on hedonic feeding behavior. Results indicate that Amp-CPP was completely blocked in the FLOX mice, but not in the GLP-1R KD(Nestin) mice following EX-4 pretreatment. Ex-4 pretreatment selectively blocked alcohol consumption in the FLOX mice, but was ineffective in altering alcohol intake in the GLP-1R KD(Nestin) mice. Notably, hedonic feeding was partially blocked in the GLP-1R KD(Nestin) mice, whereas it was abolished in the FLOX mice. The present study provides critical insights regarding the nature by which GLP-1 signaling controls reinforced behaviors and underscores the importance of both peripheral and central GLP-1R signaling for the regulation of addictive disorders.

Aversion learning can reduce meal size without taste avoidance in rats.

OBJECTIVE: Nausea and aversive food responses are commonly reported following bariatric surgery, along with post-surgical reduction in meal size. This study investigates whether a meal size limit can be conditioned by associating large meals with aversive outcomes. METHODS: In rats, the intake of meals exceeding a pre-defined size threshold was paired with lithium chloride-induced gastric illness, and the effects on self-determined food intakes and body weight were measured. RESULTS: Rats given LiCl contingent on the intake of a large meal learned to reliably reduce intake below this meal size threshold, while post-meal saline or LiCl before meals did not change meal size. It was further demonstrated that this is not a conditioned taste aversion and that this effect transferred to foods not explicitly trained. Finally, when rats received LiCl following all large meals, the number of small meals increased, but total food intake and body weight decreased. CONCLUSIONS: While further work is needed, this is the first demonstration that meal size may be conditioned, using an aversion procedure, to remain under a target threshold and that this effect is distinct from taste avoidance. Corresponding reduction in food intake and body weight suggests that this phenomenon may have implications for developing weight loss strategies and understanding the efficacy of bariatric surgery.

Insulin Sensitivity and ß-Cell Function Improve after Gastric Bypass in Severely Obese Adolescents.

OBJECTIVE: To test the hypothesis that insulin secretion and insulin sensitivity would be improved in adolescents after Roux-en-Y gastric bypass (RYGB). STUDY DESIGN: A longitudinal study of 22 adolescents and young adults without diabetes undergoing laparoscopic RYGB (mean age 17.1 ± 1.42 years; range 14.5-20.1; male/female 8/14; Non-Hispanic White/African American 17/5) was conducted. Intravenous glucose tolerance tests were done to obtain insulin sensitivity (insulin sensitivity index), insulin secretion (acute insulin response to glucose ), and the disposition index as primary outcome variables. These variables were compared over the 1 year of observation using linear mixed modeling. RESULTS: In the 1-year following surgery, body mass index fell by 38% from a mean of 61 ± 12.3 to 39 ± 8.0 kg/m(2) (P < .01). Over the year following surgery, fasting glucose and insulin values declined by 54% and 63%, respectively. Insulin sensitivity index increased 300% (P < .01), acute insulin response to glucose decreased 56% (P < .01), leading to a nearly 2-fold increase in the disposition index (P < .01). Consistent with improved ß-cell function, the proinsulin to C-peptide ratio decreased by 21% (P < .01). CONCLUSIONS: RYGB reduced body mass index and improved both insulin sensitivity and ß-cell function in severely obese teens and young adults. These findings demonstrate that RYGB is associated with marked metabolic improvements in obese young people even as significant obesity persists. TRIAL REGISTRATION: ClinicalTrials.gov: NCT00360373.

Enhanced responsiveness to selective serotonin reuptake inhibitors during lactation.

The physiology of mood regulation in the postpartum is poorly understood despite the fact that postpartum depression (PPD) is a common pathology. Serotonergic mechanisms and their dysfunction are widely presumed to be involved, which has led us to investigate whether lactation induces changes in central or peripheral serotonin (5-HT) systems and related affective behaviors. Brain sections from lactating (day 10 postpartum) and age-matched nulliparous (non-pregnant) C57BL/6J mice were processed for 5-HT immunohistochemistry. The total number of 5-HT immunostained cells and optical density were measured. Lactating mice exhibited lower immunoreactive 5-HT and intensity in the dorsal raphe nucleus when compared with nulliparous controls. Serum 5-HT was quantified from lactating and nulliparous mice using radioimmunoassay. Serum 5-HT concentrations were higher in lactating mice than in nulliparous controls. Affective behavior was assessed in lactating and non-lactating females ten days postpartum, as well as in nulliparous controls using the forced swim test (FST) and marble burying task (MBT). Animals were treated for the preceding five days with a selective serotonin reuptake inhibitor (SSRI, citalopram, 5mg/kg/day) or vehicle. Lactating mice exhibited a lower baseline immobility time during the FST and buried fewer marbles during the MBT as compared to nulliparous controls. Citalopram treatment changed these behaviors in lactating mice with further reductions in immobility during the FST and decreased marble burying. In contrast, the same regimen of citalopram treatment had no effect on these behaviors in either non-lactating postpartum or nulliparous females. Our findings demonstrate changes in both central and peripheral 5-HT systems associated with lactation, independent of pregnancy. They also demonstrate a significant interaction of lactation and responsiveness to SSRI treatment, which has important implications in the treatment of PPD. Although recent evidence has cast doubt on the effectiveness of SSRIs, these results support their therapeutic use in the treatment of PPD.

Longitudinal trends in food cravings following Roux-en-Y gastric bypass in an adolescent sample.

BACKGROUND: Food cravings are more prevalent and potentially problematic for many individuals with obesity. Initial evidence suggests that bariatric surgery has some short-term beneficial effects on cravings in adults, but little is known about the effect on adolescents or the trajectory beyond 6 months. METHODS: The purpose of the present study was to determine the longitudinal effect of Roux-en-Y gastric bypass (RYGB) on food cravings in a sample of adolescents with severe obesity (body mass index (BMI)≥40 kg/m2). Sixteen adolescents were recruited and underwent RYGB. Participants completed the Food Craving Inventory before RYGB, and 3, 6, 12, 18, and 24 months postoperatively. The present study took place in a single pediatric tertiary care hospital. RESULTS: RYGB produced a negative (cravings decreased as time increased) nonlinear trend for total food cravings as well as for each individual subscale (sweets, high fat foods, carbohydrates, fast food) over the 24-month study period. This means that while cravings decrease postsurgically, there is a decline in the slope with the line reaching asymptote at approximately 18 months. BMI change was not a significant predictor of food cravings, but low statistical power may account for this lack of significance. CONCLUSION: These findings provide preliminary evidence that RYGB decreases food cravings in adolescents.

Weight loss by calorie restriction versus bariatric surgery differentially regulates the hypothalamo-pituitary-adrenocortical axis in male rats.

Behavioral modifications for the treatment of obesity, including caloric restriction, have notoriously low long-term success rates relative to bariatric weight-loss surgery. The reasons for the difference in sustained weight loss are not clear. One possibility is that caloric restriction alone activates the stress-responsive hypothalamo-pituitary-adrenocortical (HPA) axis, undermining the long-term maintenance of weight loss, and that this is abrogated after bariatric surgery. Accordingly, we compared the HPA response to weight loss in five groups of male rats: (1) high-fat diet-induced obese (DIO) rats treated with Roux-en-Y gastric bypass surgery (RYGB, n = 7), (2) DIO rats treated with vertical sleeve gastrectomy (VSG, n = 11), (3) DIO rats given sham surgery and subsequently restricted to the food intake of the VSG/RYGB groups (Pair-fed, n = 11), (4) ad libitum-fed DIO rats given sham surgery (Obese, n = 11) and (5) ad libitum chow-fed rats given sham surgery (Lean, n = 12). Compared with Lean controls, food-restricted rats exhibited elevated morning (nadir) non-stress plasma corticosterone concentration and increased hypothalamic corticotropin-releasing hormone and vasopressin mRNA expression, indicative of basal HPA activation. This was largely prevented when weight loss was achieved by bariatric surgery. DIO increased HPA activation by acute (novel environment) stress and this was diminished by bariatric surgery-, but not pair-feeding-, induced weight loss. These results indicate that the HPA axis is differentially affected by weight loss from caloric restriction versus bariatric surgery, and this may contribute to the differing long-term effectiveness of these two weight-loss approaches.

Hippocampal lipoprotein lipase regulates energy balance in rodents.

Brain lipid sensing is necessary to regulate energy balance. Lipoprotein lipase (LPL) may play a role in this process. We tested if hippocampal LPL regulated energy homeostasis in rodents by specifically attenuating LPL activity in the hippocampus of rats and mice, either by infusing a pharmacological inhibitor (tyloxapol), or using a genetic approach (adeno-associated virus expressing Cre-GFP injected into Lpl (lox/lox) mice). Decreased LPL activity by either method led to increased body weight gain due to decreased locomotor activity and energy expenditure, concomitant with increased parasympathetic tone (unchanged food intake). Decreased LPL activity in both models was associated with increased de novo ceramide synthesis and neurogenesis in the hippocampus, while intrahippocampal infusion of de novo ceramide synthesis inhibitor myriocin completely prevented body weight gain. We conclude that hippocampal lipid sensing might represent a core mechanism for energy homeostasis regulation through de novo ceramide synthesis.

Use of bariatric outcomes longitudinal database (BOLD) to study variability in patient success after bariatric surgery.

BACKGROUND: This study was conducted to determine the contributions of various predictors to the large variations in absolute weight loss and percent body mass index (BMI) loss after bariatric surgery. METHODS: The data source was the Bariatric Outcomes Longitudinal Database(SM) by the Surgical Review Corporation. Eligibility criteria included a first bariatric surgery for adjustable gastric band (AGB), Roux-en-Y gastric bypass (RYBG), or sleeve gastrectomy (SG) between January 2007 and February 2010; age 21 years or older; presurgery BMI > 30 kg/m2; and at least one preoperative visit within 6 months and at least one postoperative visit 30 days or more after surgery. Potential predictor variables included procedural details, patient demographics, comorbidities, and prior surgical history. Linear regression models of absolute weight loss and %BMI loss were fitted at 12, 18, and 24 months. The 12-month absolute weight loss endpoint was then chosen for a more in-depth analysis of variability through variable transformations and separate models by procedure. RESULTS: A total of 31,443 AGB, 40,352 RYGB, and 2,194 SG patients met all inclusion criteria. Regression models explained 37 to 55% of the variability in %BMI loss and 52 to 65% of variability in absolute weight loss. The key predictors for absolute weight loss at 12 months were procedure (44.8%) and baseline weight (18.5%), with 34.2% of the variability unexplained. Other significant predictors, each of which accounted for <1% of variability, included age, race, and diabetes. CONCLUSIONS: Research on additional sources of variability is still needed to help explain the remaining differences in outcomes after bariatric surgery.

Acute administration of unacylated ghrelin has no effect on Basal or stimulated insulin secretion in healthy humans.

Unacylated ghrelin (UAG) is the predominant ghrelin isoform in the circulation. Despite its inability to activate the classical ghrelin receptor, preclinical studies suggest that UAG may promote ß-cell function. We hypothesized that UAG would oppose the effects of acylated ghrelin (AG) on insulin secretion and glucose tolerance. AG (1 µg/kg/h), UAG (4 µg/kg/h), combined AG+UAG, or saline were infused to 17 healthy subjects (9 men and 8 women) on four occasions in randomized order. Ghrelin was infused for 30 min to achieve steady-state levels and continued through a 3-h intravenous glucose tolerance test. The acute insulin response to glucose (AIRg), insulin sensitivity index (SI), disposition index (DI), and intravenous glucose tolerance (kg) were compared for each subject during the four infusions. AG infusion raised fasting glucose levels but had no effect on fasting plasma insulin. Compared with the saline control, AG and AG+UAG both decreased AIRg, but UAG alone had no effect. SI did not differ among the treatments. AG, but not UAG, reduced DI and kg and increased plasma growth hormone. UAG did not alter growth hormone, cortisol, glucagon, or free fatty acid levels. UAG selectively decreased glucose and fructose consumption compared with the other treatments. In contrast to previous reports, acute administration of UAG does not have independent effects on glucose tolerance or ß-cell function and neither augments nor antagonizes the effects of AG.

GLP-1R responsiveness predicts individual gastric bypass efficacy on glucose tolerance in rats.

Several bariatric operations are currently used to treat obesity and obesity-related comorbidities. These vary in efficacy, but most are more effective than current pharmaceutical treatments. Roux-en-Y gastric bypass (RYGB) produces substantial body weight (BW) loss and enhanced glucose tolerance, and is associated with increased secretion of the gut hormone glucagon-like peptide 1 (GLP-1). Given the success of GLP-1-based agents in lowering blood glucose levels and BW, we hypothesized that an individual sensitivity to GLP-1 receptor agonism could predict metabolic benefits of surgeries associated with increased GLP-1 secretion. One hundred ninety-seven high-fat diet-induced obese male Long-Evans rats were monitored for BW loss during exendin-4 (Ex4) administration. Stable populations of responders and nonresponders were identified based on Ex4-induced BW loss and GLP-1-induced improvements in glucose tolerance. Subpopulations of Ex4 extreme responders and nonresponders underwent RYGB surgery. After RYGB, responders and nonresponders showed similar BW loss compared with sham, but nonresponders retained impaired glucose tolerance. These data indicate that the GLP-1 response tests may predict some but not all of the improvements observed after RYGB. These findings present an opportunity to optimize the use of bariatric surgery based on an improved understanding of GLP-1 biology and suggest an opportunity for a more personalized therapeutic approach to the metabolic syndrome.

Longitudinal trends in hedonic hunger after Roux-en-Y gastric bypass in adolescents.

BACKGROUND: Initial outcome studies have reported that Roux-en-Y gastric bypass (RYGB) is safe and efficacious for adolescents with extreme obesity. Although rapid weight loss is seen initially, data also show that modest weight regain typically occurs as early as the second postoperative year. The contribution of various psychological factors, including hedonic hunger, to postoperative weight regain has not previously been studied in adolescents. The objective of this study was to examine the variability in hedonic hunger and body mass index (BMI) over the initial 2-year period of weight loss and modest weight regain in adolescent RYGB recipients. METHODS: A total of 16 adolescents completed the Power of Food Scale before surgery and at 3, 6, 12, 18, and 24 months postoperatively. Height and weight were measured at each time point, from which BMI was calculated. RESULTS: Nonlinear trends were observed for time on both overall hedonic hunger and hedonic hunger specifically related to food available in the adolescent's environment. The BMI reduction during the first 18 months postoperatively was paralleled by reduction in hedonic hunger; increases in hedonic hunger also paralleled the modest BMI increase at 24 months. In growth analysis, significant power gains are available to models using 4 or more points of data. However, only large effect sizes that are>.85 were detectable with a sample of 16 patients. CONCLUSION: These data provide preliminary evidence that hedonic hunger is in need of further study in adolescent patients receiving RYGB both preoperatively and postoperatively.

Roux en Y gastric bypass increases ethanol intake in the rat.

Roux en Y gastric bypass (RYGB) surgery is currently the most effective therapy employed to treat obesity and its associated complications. In addition to weight loss and resolution of metabolic syndromes, such as diabetes, the RYGB procedure has been reported to increase alcohol consumption in humans. Using an outbred rodent model, we demonstrate that RYGB increases postsurgical ethanol consumption, that this effect cannot be explained solely by postsurgical weight loss and that it is independent of presurgical body weight or dietary composition. Altered ethanol metabolism and postsurgical shifts in release of ghrelin were also unable to account for changes in alcohol intake. Further investigation of the potential physiological factors underlying this behavioral effect identified altered patterns of gene expression in brain regions associated with reward following RYGB surgery. These findings have important clinical implications as they demonstrate that RYGB surgery leads directly to increased alcohol intake in otherwise alcohol nonpreferring rat and induces neurobiological changes in brain circuits that mediate a variety of appetitive behaviors.

Antipsychotic medications, glutamate, and cell death: a hidden, but common medication side effect?

We hypothesize the interaction between antipsychotic medications and regulation of extracellular glutamate which has gone largely unnoticed in the medical community has significant clinical importance. Typical antipsychotic medications such as haloperidol elevate extracellular glutamate because they exert antagonist effects on dopamine D(2) and serotonin 5HT(1A) receptors. In contrast, serotonin 5HT(2A) receptor antagonists inhibit glutamate release. Glutamate is potentially excitotoxic through effects on ionotropic receptor channels and may exert synergistic effects with other neurotoxic pathways. In contrast to typical antipsychotic drugs, pharmacological properties of atypical antipsychotic medications at dopamine D(2), serotonin 5HT(1A) and 5HT(2A) receptors limit extracellular glutamate and may theoretically be neuroprotective in certain clinical settings. In this review we discuss three common clinical settings in which typical antipsychotic medications may potentiate neurotoxicity by elevating extracellular glutamate. The most common clinical setting, hypoglycemia during combined use of antipsychotic medications and insulin, presents a theoretical risk for 35 million diabetic patients worldwide using antipsychotic medications. Antipsychotic medication treatment during hypoxic episodes in the intensive care unit and following traumatic brain injury are two other common clinical settings in which this interaction poses theoretical risk. Further study is needed to test hypothesized risk mechanisms, and determine clinical and epidemiological consequences of these exposures.

Moderate high fat diet increases sucrose self-administration in young rats.

We have previously reported that a moderately high fat diet increases motivation for sucrose in adult rats. In this study, we tested the motivational, neurochemical, and metabolic effects of the high fat diet in male rats transitioning through puberty, during 5-8 weeks of age. We observed that the high fat diet increased motivated responding for sucrose, which was independent of either metabolic changes or changes in catecholamine neurotransmitter metabolites in the nucleus accumbens. However, AGRP mRNA levels in the hypothalamus were significantly elevated. We demonstrated that increased activation of AGRP neurons is associated with motivated behavior, and that exogenous (third cerebroventricular) AGRP administration resulted in significantly increased motivation for sucrose. These observations suggest that increased expression and activity of AGRP in the medial hypothalamus may underlie the increased responding for sucrose caused by the high fat diet intervention. Finally, we compared motivation for sucrose in pubertal vs. adult rats and observed increased motivation for sucrose in the pubertal rats, which is consistent with previous reports that young animals and humans have an increased preference for sweet taste, compared with adults. Together, our studies suggest that background diet plays a strong modulatory role in motivation for sweet taste in adolescent animals.

Omega-3 fatty acid deficiency augments risperidone-induced hepatic steatosis in rats: positive association with stearoyl-CoA desaturase.

Psychiatric patients frequently exhibit long-chain n-3 (LCn-3) fatty acid deficits and elevated triglyceride (TAG) production following chronic exposure to second generation antipsychotics (SGAs). Emerging evidence suggests that SGAs and LCn-3 fatty acids have opposing effects on stearoyl-CoA desaturase-1 (SCD1), which plays a pivotal role in TAG biosynthesis. Here we evaluated whether low LCn-3 fatty acid status would augment elevations in rat liver and plasma TAG concentrations following chronic treatment with the SGA risperidone (RSP), and evaluated relationships with hepatic SCD1 expression and activity indices. In rats maintained on the n-3 fatty acid-fortified (control) diet, chronic RSP treatment significantly increased liver SCD1 mRNA and activity indices (18:1/18:0 and 16:1/16:0 ratios), and significantly increased liver, but not plasma, TAG concentrations. Rats maintained on the n-3 deficient diet exhibited significantly lower liver and erythrocyte LCn-3 fatty acid levels, and associated elevations in LCn-6/LCn-3 ratio. In n-3 deficient rats, RSP-induced elevations in liver SCD1 mRNA and activity indices (18:1/18:0 and 16:1/16:0 ratios) and liver and plasma TAG concentrations were significantly greater than those observed in RSP-treated controls. Plasma glucose levels were not altered by diet or RSP, and body weight was lower in RSP- and VEH-treated n-3 deficient rats. These preclinical data support the hypothesis that low n-3 fatty acid status exacerbates RSP-induced hepatic steatosis by augmenting SCD1 expression and activity.

Cyclocreatine treatment improves cognition in mice with creatine transporter deficiency.

The second-largest cause of X-linked mental retardation is a deficiency in creatine transporter (CRT; encoded by SLC6A8), which leads to speech and language disorders with severe cognitive impairment. This syndrome, caused by the absence of creatine in the brain, is currently untreatable because CRT is required for creatine entry into brain cells. Here, we developed a brain-specific Slc6a8 knockout mouse (Slc6a8-/y) as an animal model of human CRT deficiency in order to explore potential therapies for this syndrome. The phenotype of the Slc6a8-/y mouse was comparable to that of human patients. We successfully treated the Slc6a8-/y mice with the creatine analog cyclocreatine. Brain cyclocreatine and cyclocreatine phosphate were detected after 9 weeks of cyclocreatine treatment in Slc6a8-/y mice, in contrast to the same mice treated with creatine or placebo. Cyclocreatine-treated Slc6a8-/y mice also exhibited a profound improvement in cognitive abilities, as seen with novel object recognition as well as spatial learning and memory tests. Thus, cyclocreatine appears promising as a potential therapy for CRT deficiency.