Roux-en-Y gastric bypass surgery changes food reward in rats.

CONTEXT: Roux-en-Y gastric bypass surgery (RYGB) is currently the most effective treatment for morbid obesity, and clinical studies suggest that RYGB patients change food preferences and the desire to eat. OBJECTIVE: To examine hedonic reactions to palatable foods and food choice behavior in an established rat model of RYGB. METHODS AND DESIGN: Male Sprague-Dawley (SD) rats and selected line obesity-prone rats that were rendered obese on a high-fat diet underwent RYGB or sham surgery and were tested for 'liking' and 'wanting' of palatable foods at different caloric densities 4-6 months after surgery. RESULTS: Compared with sham-operated (obese) and age-matched lean control rats, RYGB rats of both models exhibited more positive orofacial responses to low concentrations of sucrose but fewer to high concentrations. These changes in 'liking' by RYGB rats were translated into a shift of the concentration-response curve in the brief access test, with more vigorous licking of low concentrations of sucrose and corn oil, but less licking of the highest concentrations. The changes in hedonic evaluation also resulted in lower long-term preference/acceptance of high-fat diets compared with sham-operated (obese) rats. Furthermore, the reduced 'wanting' of a palatable reward in the incentive runway seen in sham-operated obese SD rats was fully restored after RYGB to the level found in lean control rats. CONCLUSIONS: The results suggest that RYGB leads to a shift in hedonic evaluation, favoring low over high calorie foods and restores obesity-induced alterations in 'liking' and 'wanting'. It remains to be determined whether these effects are simply due to weight loss or specific changes in gut-brain communication. Given the emerging evidence for modulation of cortico-limbic brain structures involved in reward mechanisms by gut hormones, RYGB-induced changes in the secretion of these hormones could potentially be mediating these effects.

Reversible suppression of food reward behavior by chronic mu-opioid receptor antagonism in the nucleus accumbens.

Overindulgence in easily available energy-dense palatable foods is thought to be an important factor in the current obesity epidemic but the underlying neural mechanisms are not well understood. Here we demonstrate that mu-opioid receptor signaling in the nucleus accumbens may be important. Protracted suppression of endogenous mu-opioid receptor signaling focused on the nucleus accumbens shell for several days by means of microinjected beta-funaltrexamine (BFNA) diminished both "liking" of sucrose, as indicated by fewer positive hedonic orofacial responses, and the incentive reinforcement value ("wanting") of a food reward, as indicated by lower completion speed and increased time being distracted in the incentive runway. BFNA-treatment also decreased responding to sucrose and corn oil in the brief access lick paradigm, a test measuring a combination of mainly taste-guided "liking" and low-effort "wanting", as well as 4 h intake of sucrose solution. These effects were not due to nonspecific permanent neuronal changes, as they were fully reversible. We conclude that endogenous mu-opioid signaling in the nucleus accumbens is necessary for the full display of palatable food-induced hyperphagia through mechanisms including hedonic, motivational, and reinforcement processes. Development of obesity could be the result of predisposing innate differences in these mechanisms or overstimulation of these mechanisms by external factors.

Development of a water-escape motivated version of the Stone T-maze for mice.

Mice provide a highly valuable resource for investigating learning and memory processes; however, many of the established tasks for evaluating learning and memory were developed for rats. Behaviors of mice in these tasks appear to be driven by different motivational factors, and as a result, they often do not perform reliably on tasks involving rewards traditionally used for rats. Because of difficulties in measuring learning and memory in mice as well as the need to have a task that can reliably measure these behavioral processes, we have developed a mouse version of the Stone T-maze utilizing what appears to be the primary motivation of mice, escape to a safe location. Specifically, we have constructed a task that requires the mouse to wade through water to reach a dark and dry goal box. To escape this aversive environment, the Stone T-maze requires learning the correct sequence of 13 left and right turns to reach the goal box. Through a series of experiments examining a variety of protocols, it was found that mice will reliably perform this task. This task can be used to assess learning and memory without the potential performance confounds that can affect performance of mice in other tasks. We believe this task offers a valuable new tool for evaluating learning and memory in mice not previously available to researchers.

Extended fear conditioning reveals a role for both N-methyl-D-aspartic acid and non-N-methyl-D-aspartic acid receptors in the amygdala in the acquisition of conditioned fear.

Pavlovian conditioning is a useful tool for elucidating the neural mechanisms involved with learning and memory, especially in regard to the stimuli associated with aversive events. The amygdala has been repeatedly implicated as playing a significant role in the acquisition and expression of fear. If the amygdala is critical for the acquisition of fear, then it should contribute to this processes regardless of the parameters used to induce or evaluate conditioned fear. A series of experiments using reversible inactivation techniques evaluated the role of the amygdala in the acquisition of conditioned fear when training was conducted over several days in rats. Fear-potentiated startle was used to evaluate the acquisition of conditioned fear. Pretraining infusions of N-methyl-d-aspartic acid (NMDA) or non-NMDA receptor antagonists alone into the amygdala interfered with the acquisition of fear early in training, but not later. Pretraining infusions of a cocktail consisting of both an NMDA and non-NMDA antagonist interfered with the acquisition of conditioned fear across all days of training. Taken together these results suggest the amygdala may potentially be critical for the acquisition of conditioned fear regardless of the parameters utilized.

Acquisition of conditioned taste aversion is impaired in the amyloid precursor protein/presenilin 1 mouse model of Alzheimer's disease.

Research into the underlying mechanisms of cognitive dysfunction in Alzheimer's disease (AD) has relied traditionally on tasks such as the water maze which evaluate spatial learning and memory. Since non-spatial forms of memory are also disrupted by AD, it is critical to establish other paradigms capable of investigating these deficits. Utilizing a non-spatial learning task, acquisition of conditioned taste aversion (CTA) was evaluated in a mouse model of AD. This line of transgenic mice encode a mutated allele of the human amyloid precursor protein (APP) and presenilin 1 (PS1) genes and exhibit extensive amyloid plaque deposition in the brain by 6-7 mo of age. Compared with wild-type mice, 10-17 month old APP/PS1 mice failed to acquire CTA to saccharin. Mice that only possessed one of the two mutations were able to acquire CTA to the saccharin. In 2-5 month old APP/PS1 mice acquisition of CTA was disrupted despite the lack of extensive plaque deposition. However, further analysis indicated a potential gender difference in both the CTA deficit and onset of plaque deposition with females showing greater conditioned aversion.

Facilitation of stimulus detection performance of rats with d-amphetamine: a function of dose and level of training.

Conditions under which amphetamine may facilitate stimulus detection task choice performance in rats were investigated. Rats (n=15) were trained in a two-choice, light-detection task to three successively more stringent criterion levels of task training (minimal, intermediate, and extended) and then tested after administration of saline, 0.25, 0.50, and 0.75 mg/kg d-amphetamine (AMP). For each training level, baseline levels of choice accuracy were maintained at approximately 82% by manipulating the animals' cue duration. No aspect of performance was enhanced by any dose of AMP after minimal criteria training, and there was a dose-dependent decrease in the number of trials completed. After the intermediate level of training, the 0.25 mg/kg dose of AMP reliably increased choice accuracy, there was no reliable change in choice reaction time, and there was a dose-dependent decrease in the number of trials completed. After the extended training, the 0.25 mg/kg dose of AMP reliably increased choice response accuracy, the 0.25 and 0.50 mg/kg doses of AMP reliably decreased choice reaction time, and there was no reliable change in the number of trials completed at any dose of AMP. These results support the contention that psychostimulants can facilitate the choice performance of rats in stimulus detection tasks if an appropriately low dose is used and the animal's behavior is strongly controlled by the stimulus-reinforcement contingencies of the task.

Fluoxetine alters the effects of cocaine on vigilance task performance of rats.

The potential modulating influence of fluoxetine (FLU) on the effects of cocaine (COC) on vigilance task performance was explored. Rats were trained in a discrete-trial task in which pressing one of two levers was reinforced by food, with the correct lever indicated by the position of a briefly illuminated light. Tests with FLU (2.5, 5.0, and 10.0 mg/kg) revealed no significant effects of FLU on mean choice accuracy, log choice reaction time, or number of omission trials; however, 10.0 mg/kg FLU did produce a small but reliable increase in mean log food retrieval latency. The effects of COC (1.25, 2.5 and 10.0 mg/kg) were then assessed following pretreatment with saline or FLU (2.5 and 10.0 mg/kg). COC increased mean choice accuracy, with maximal performance enhancement occurring with 2.5 mg/kg COC; mean log choice reaction time was decreased by all three doses of COC, although there was considerable within-subject variability at the 10.0 mg/kg dose of COC. Pretreatment with FLU reversed both of these performance-enhancing effects of COC in a dose-dependent fashion. Log food retrieval latency was not significantly affected by the lower doses of COC and was significantly increased by the 10.0 mg/kg dose of COC. FLU and COC appeared to interact in an additive fashion with this measure. The number of omission trials per session was significantly increased by 10.0 mg/kg COC--an effect that was not significantly altered by FLU pretreatment. These results support previous studies indicating that acute FLU exposure can reduce many of COC's properties that may contribute to COC's efficacy as a positive reinforcer.