KNOCKOUT OF P11 ATTENUATES COCAINE REWARD AND REINSTATEMENT IN MALES BUT NOT IN FEMALE MICE. Cocaines enhancement of dopamine signaling is crucial for its rewarding effects but its serotonergic effects are also relevant (Belzung et al. 2000;Neumaier et al. 2002). Here we examined the role of the protein p11, which recruits serotonin receptors (5HT1B and 5HT4) to the cell surface, in cocaine reward. METHODS: For this purpose we tested p11 +/+ (wildtype or WT) and p11 -/- (knockout or KO) male and female mice for cocaine conditioned place preference (CPP) and its reinstatement at different abstinence times after 8 days of extinction and 28 days of being home-caged. RESULTS: All mice showed significant cocaine CPP;but in the males the KO showed significantly lower CPP than the WT (44%;p=0.054) and these differences were more accentuated 28 days after extinction (p=0.004). In contrast, in the females there were no differences between KO and WT mice. Gender differences in CPP were observed 28 days after extinction in WT mice (males had 81% greater CPP than females;p = 0.024) but not in KO mice. Locomotor activity was greater for males than for females but there were no differences between WT and KO. CONCLUSIONS: These results reveal sex differences on the role of p11 in modulating cocaine CPP and its persistence during extinction and reinstatement. Specifically absence of p11 appears to confer protection to cocaine CPP in male but not in female mice suggesting that 5HT1B and 5HT4 mediated serotonin signaling contributes to cocaines rewarding responses in male but not female mice. The greater CPP in males than females WT mice but not in KO mice, suggests that p11 presumably though its enhancement of serotonin signaling contributes to sex differences in cocaine reward. THE EFFECTS OF GASTRIC BYPASS AND A HIGH FAT DIET ON FOOD REWARD ANTICIPATION. The Roux-en-Y gastric bypass (RYGB) is an effective treatment for morbid obesity. However little is known about the impact of RYGB on the brain responses to food reward. Here we examined the effects of RYGB on the anticipatory responses to palatable versus regular food. METHODS: Rodents were conditioned to chambers paired with bacon or chow, and then tested for conditioned place preference (CPP) for the bacon-paired chamber, relative to the chow-paired chamber. After CPP, animals were placed in either the bacon- or chow-paired chamber without the food stimulus, and brain-glucose utilization was measured using microPET and FDG. RESULTS: Bacon facilitated CPP for the bacon paired chamber only in RYGB rats that had stable weights following surgery. Regional brain metabolism was higher in response to cues predicting chow or bacon in all high-fat fed cohorts compared to chow-fed Sham-ND rats and the weight-stable RYGB high-fat fed rats had the greatest regional activation to the bacon cues. Bacon CPP led to greater activation in frontal cortex, striatum, thalamus and hypothalamus, which are brain regions involved in reward and motivation for food. Sham-ND animals had decreased brain activation in all brain areas examined, while all other animals had heightened activation, with the RYGB group having the highest but most variable activation. CONCLUSION: These findings suggest that the RYGB rats show increased food anticipation and related brain activation in brain reward areas to food cues associated with highly palatable food. Similar studies may help us better understand the causal relationship between altered brain functions and hormonal-behavioral improvements following RYGB. CHRONIC EXERCISE BLOCKS REINSTATEMENT OF NICOTINE PREFERENCE IN ADOLESCENT MICE. Clinical and preclinical studies have given evidence of the beneficial effects of exercise in preventing relapse and in altering the rewarding effects of nicotine in adult smokers and in adult rodents. However the effects of exercise on nicotine relapse in adolescence have not been valuated. Here, we assessed the effects of chronic forced exercise on conditioning to nicotine after reinstatement following its withdrawal in adolescent mice. METHODS: Male mice were exposed to nicotine injections in adolescence (PN 28-42), and were either exposed to a six-week abstinence from nicotine, or abstinence concurrent with low or moderate intensity exercise (PN 52-94). The exercise program consisted of forced treadmill running (ten meters per minute for five days per week for six weeks), either for half an hour (low intensity) or an hour (moderate intensity). RESULTS: After six weeks of abstinence nicotine induced strong reinstatement of nicotine CPP in the sedentary control group (53% increase from baseline;p<0.05) but not in the exercise treated groups. Interestingly in the sedentary mice but not in the exercised animals nicotine CPP during reinstatement was inversely correlated with locomotor activity (r=-0.6, p=0.02) such that mice that moved the most showed less CPP than those that moved the least. CONCLUSION: These data provides evidence that chronic low to moderate aerobic exercise blocks nicotine reinstatement of CPP in adolescent rodents, giving evidence of protective effects of physical activity in nicotine relapse. The findings suggest that exercise in adolescents may be helpful in smoking cessation programs. MAPPING BRAIN METABOLIC CONNECTIVITY IN AWAKE RATS WITH MICROPET AND OPTOGENETIC STIMULATION. Optogenetic stimulation (OGS) in combination with fMRI has been used to investigate functional connectivity in the rodent brain (Lee and Deisseroth, 2012);however, this requires the use of anesthesia, which affects neuronal activity. PET and 18F 2-fluoro-2-deoxy-D-glucose (FDG), allow to non-invasively measure regional brain glucose metabolism marker of brain activity), in the awake rodent. Here we tested the sensitivity of PET FDG to OGS of the NAc and corroborated activation with c-Fos mapping. METHODS: Male Sprague Dawley rats were infused with an Adeno-associated virus serotype 2 (AAV2)-hsyn-ChR2-EYFP (n=8/group) or AAV2-GFP control virus (n=9/group) into the right NAc core. Two weeks later each rat was scanned twice using FDG-PET, one week apart (counterbalanced design): once at baseline (optical fiber attached but no stimulation applied) and once following OGS. Starting five minutes before and continuing through the FDG uptake period rats were stimulated with blue light after which they were anesthetized and scanned. The brain was also harvested to assess c-Fos immunofluorescence in the NAc following OGS exposures. RESULTS: We demonstrated not only increases in brain glucose metabolism that correlated with c-Fos expression in the region of stimulation (R=0.77, p<0.01), but also metabolic increases in the ipsilateral striatum, periacqueductal gray, and somatosensory cortex, and in contralateral amgydala, ventral pallidum, globus pallidus, and hippocampus, as well as decreases in metbaolism in regions of the default mode network (restroplenial cortex and cingulate gyrus) and in secondary motor cortex. CONCLUSION: These findings are consistent with optogenetic excitation of the area of stimulation (NAc), as well as with stimulatory and inhibitory effects on downstream regions. They also confirm the utility of PET imaging to monitor connectivity in the awake rodent brain.

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National Institute on Alcohol Abuse and Alcoholism
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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
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
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
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
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
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
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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