GASTRIC BYPASS INCREASES ETHANOL AND WATER CONSUMPTION IN DIETARY OBESE RATS Roux-en-Y gastric bypass surgery (RYGB) is an effective treatment for morbid obesity. However, reports of increased alcohol abuse after RYGB resulted in recommendations to exclude patients with alcohol abuse histories from RYGB. Here we examined if RYGB modifies ethanol intake. Methods: Sprague Dawley rats fed a high-fat diet underwent either gastric bypass or a sham operation. After surgery the rats were given a two-bottle choice between varying concentrations of ethanol solution (maximum ethanol concentration of 8% v/v) and water and monitored ethanol intake (g/kg) and % preference compared to water. Two controls were used, a sham operated group who was pair-fed the same amount of food as the gastric bypass rats (to control for food intake;obese control) and a control group receiving normal rat chow (lean control with no surgery). Results: RYGB rats daily consumption of ethanol averaged 2 g/kg (2% concentration) and 3.8 g/kg (4% concentration), twice as much as sham-operated obese controls and 50% more than normal-diet lean controls during habituation. In contrast, obese controls drank on average 1 g/kg of ethanol (2 and 4%), significantly less (50%) than lean controls. RYGB rats when given higher ethanol concentrations (6 and 8%) or no ethanol drank significantly more water than lean and obese controls (66 and 100% respectively) and their enhanced total fluid intake (water + alcohol) was associated with increased food intake, which was significantly higher than in lean (66% more calories;food + alcohol) and obese controls (44% more calories). Conclusions: These findings support an enhanced sensitivity to alcohols rewarding effects (low doses) in part from its caloric content. Lower alcohol intake in obese controls suggests that metabolic adaptations during obesity (i.e leptin resistance) may interfere with alcohols rewarding effects and that their recovery with RYGB may remove this protective effect. The overall enhancement of consummatory behaviors suggests that RYGB may facilitate alcohol abuse as an alternative source of calories that in vulnerable individuals can lead to addiction. It also highlights the possibility that in some individuals the rewarding effects of alcohol are driven by caloric content and not just pharmacological actions. EFFECTS OF SUBCHRONIC NICOTINE DURING ADOLESCENCE IN A PRECLINICAL MODEL OF DEPRESSION: GENDER EFFECTS Smoking initiation usually occurs during adolescence and, in those vulnerable it can persist throughout adulthood. Smoking is frequently co-morbid with depression and this association is more prevalent in women than in men. This has led to questioning whether co-morbidity of smoking and depression could be bidirectional that is, depression increases risk of smoking but also that smoking initiation early in life may increase risk for depression. To test this possibility we assess the effects of nicotine exposure during adolescence in male and female mice on the Forced Swim Test (FST), which is used as an animal model of depression. Methods: Mice (C57 BL/6) received daily saline or nicotine injections during adolescence (4 weeks of age) for 2 weeks and were then examined with the FST either one or thirty days after the last injection (adolescence and young adulthood, respectively). Results: In adolescence there were no sex differences in FST scores in saline exposed mice whereas in young adulthood female saline exposed mice had significantly lower FST scores than their male counterparts. Exposure to chronic nicotine showed that after one day of discontinuation, female mice showed a significant decrease in FST scores (22%) and in locomotor activity (12%) whereas nicotine exposed male mice did not. In contrast, when tested 30 days after nicotine discontinuation, the male, but not the female mice, showed a significant decrease in FST scores (26%);the differences in locomotor activity were not significant. Conclusions: The results suggest that while female mice are prone to short lasting depressive-like behaviors after acute nicotine withdrawal, chronic nicotine exposure during the adolescent period increased the risk for adult depressive-like behavior in the adult males, but not in the females. Similar studies in different strains of mice are necessary to assess the overall generalization of these findings and epidemiological studies evaluating the interaction between sex, adolescent nicotine exposure and risk for depression in adulthood are required to assess its clinical relevance. EFFECTS OF CHRONIC EXPOSURE TO METHYLPHENIDATE ON BONE PHYSIOLOGY IN ADOLESCENT RATS Methylphenidate (MP) is a psychostimulant widely prescribed to treat Attention Deficit Hyperactivity Disorder (ADHD). Though generally well tolerated, growth deficits have been reported in children and adolescents taking MP. This study was designed to elucidate the skeletal effects of chronic MP treatment in adolescent rats. Methods: Male, 4-week-old rats received one of two doses of MP Low (4/10 mg) or High (30/60) orally that emulated plasma concentration achieved by low and clinical high doses of slow release formulation of OROS MP. A third group was left untreated. After 12 weeks, half were sacrificed and the rest were recovered, untreated, for 5 weeks. Femora and L5 vertebra were analyzed using calipers, densitometry, and mechanical testing. Results: Immediately after treatment, MP decreased femoral anterior-posterior diameter (5% MP Low, 9% MP High), bone mineral density (6% MP High), bone mineral content (9% MP High), ultimate force (20% MP High), and energy to failure (20% MP Low, 33% MP High). However, after 12 week recovery no significant differences were seen. In contrast, vertebra did not differ at either time-point. Conclusion: Chronic MP treatment during adolescence resulted in smaller, less mineralized, and weaker bones at an appendicular site, but did not affect the axial site and the effects were more pronounced for the larger dose. Although these effects were ameliorated within 5 weeks, these data suggest that adolescents taking MP may have an increased risk for long bone fractures. REGIONAL BRAIN METABOLIC RESPONSES TO FOOD CONDITIONED CUES PREDICTS FOOD PREFERENCE Expectations of reward triggered in part by conditioning processes influence subsequent approach behaviors. Here we assess if differences in expectation to food reward contribute to individual variations on its consumption. Methods: We used 18FDG and PET to measure brain glucose metabolism (marker of brain function) and assessed the correlation between regional metabolism during exposure to conditioned environments to two distinct foods stimuli (bacon and chow) and the CPP for each stimulus. Male adult rats where conditioned for 30 min in contextually distinct chambers to expect either chow (4 days) or bacon (4 days) and chow or bacon were provided 20 min into the conditioning session so as to allow for the cues to be associated with the expectation of the reward. Results: Rats showed variability in CPP to food expectation (some rats preferred bacon and others chow) but successfully paired the cues with stimulus delivery. Expectation to bacon activated several regions from the brain reward/motivation and memory/conditioning circuits more than expectation to chow. Individual preference for bacon and chow-paired chambers was positively correlated with metabolic activation in regions associated with reward and conditioning (caudate putamen, orbital cortex, hypothalamus) and with arousal (thalamus). Conclusion: These results suggest that food preference reflects in part individual differences in sensitivity to conditioned food stimuli.

Project Start
Project End
Budget Start
Budget End
Support Year
8
Fiscal Year
2011
Total Cost
$1,755,657
Indirect Cost
Name
National Institute on Alcohol Abuse and Alcoholism
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DUNS #
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Grady, Deborah L; Thanos, Panayotis K; Corrada, Maria M et al. (2013) DRD4 genotype predicts longevity in mouse and human. J Neurosci 33:286-91
Thanos, Panayotis K; Robison, Lisa; Nestler, Eric J et al. (2013) Mapping brain metabolic connectivity in awake rats with ?PET and optogenetic stimulation. J Neurosci 33:6343-9
Delis, Foteini; Thanos, Panayotis K; Rombola, Christina et al. (2013) Chronic mild stress increases alcohol intake in mice with low dopamine D2 receptor levels. Behav Neurosci 127:95-105
Hajnal, Andras; Thanos, Panayotis K; Volkow, Nora D (2013) Notes on ""roux en y gastric bypass increases ethanol intake in the rat"" by Davis et al. Obes Surg 23:1317
Saint-Preux, F; Bores, L R; Tulloch, I et al. (2013) Chronic co-administration of nicotine and methamphetamine causes differential expression of immediate early genes in the dorsal striatum and nucleus accumbens of rats. Neuroscience 243:89-96
Thanos, Panayotis K; Robison, Lisa S; Robinson, John K et al. (2013) Obese rats with deficient leptin signaling exhibit heightened sensitivity to olfactory food cues. Synapse 67:171-8
Thanos, Panayotis K; Stamos, Joshua; Robison, Lisa S et al. (2013) Daily treadmill exercise attenuates cocaine cue-induced reinstatement and cocaine induced locomotor response but increases cocaine-primed reinstatement. Behav Brain Res 239:8-14
Hajnal, Andras; Zharikov, Alevtina; Polston, James E et al. (2012) Alcohol reward is increased after Roux-en-Y gastric bypass in dietary obese rats with differential effects following ghrelin antagonism. PLoS One 7:e49121
Thanos, Panayotis K; Subrize, Mike; Delis, Foteini et al. (2012) Gastric bypass increases ethanol and water consumption in diet-induced obese rats. Obes Surg 22:1884-92
Ren, H; Du, C; Yuan, Z et al. (2012) Cocaine-induced cortical microischemia in the rodent brain: clinical implications. Mol Psychiatry 17:1017-25

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