20-mg Pellets Research Articles

Proopiomelanocortin projections to the nucleus accumbens modulate acquisition and maintenance of operant palatable pellet administration in mice

Obesity is a crisis in the United States, producing many co-morbid diseases that can drastically decrease quality of life. While diet is a major focus for therapeutic intervention, the need to understand underlying appetitive neurocircuitry persists. Proopiomelanocortin (POMC) peptides are well-known for their anorexigenic activity, but also mediate reward and learning. The nucleus accumbens (NAcc) is best known for its role in reward-based learning, but the contribution of POMC projections to NAcc on feeding are controversial since the two major POMC-derived peptides (β-endorphin and α-MSH) have opposite effects on food intake. Our objective was to determine the effect of stimulating POMC projections in the NAcc on acquisition and maintenance of operant self-administration of a palatable food. Adult POMCCre mice were microinjected into the NAcc with a Cre-dependent retrograde adeno-associated viral vector expressing Gq Designer Receptors Exclusively Activated by Designer Drugs (DREADDs). Mice were trained to self-administer palatable 20-mg pellets in daily operant sessions. Acquisition of self-administration (fixed ratio 30) and baseline self-administration were measured in daily sessions, with mice receiving injections of either JHU37152 (DREADD agonist) or saline (i.p.) 15 min prior to the sessions. POMC neuron stimulation (JHU injection) before training sessions produced a significant increase in rate of acquisition and accuracy compared to the saline treated group, with no significant effect on rewards earned. Removal of POMC neuron stimulation before sessions initially reduced consumption with a gradual increase in responding for reinforcer over 3 days of saline injections. Reinstatement of POMC neuron stimulation (JHU) before the session resulted in a significant decrease in responding and rewards earned. These results suggest a complex role of POMC peptides within the NAcc that increase reward learning for a novel palatable food while decreasing consumption of the reinforcer following experience with it.

Natural food intake patterns have little synchronizing effect on peripheral circadian clocks

BackgroundCircadian rhythms across mammalian tissues are coordinated by a master clock in the suprachiasmatic nucleus (SCN) that is principally entrained by light-dark cycles. Prior investigations have shown, however, that time-restricted feeding (TRF)—daily alternation of fasting and food availability—synchronizes peripheral clocks independent of the light-dark cycle and of the SCN. This has led to the idea that downstream peripheral clocks are entrained indirectly by food intake rhythms. However, TRF is not a normal eating pattern, and it imposes non-physiologic long fasts that rodents do not typically experience. Therefore, we tested whether normal feeding patterns can phase-shift or entrain peripheral tissues by measuring circadian rhythms of the liver, kidney, and submandibular gland in mPer2Luc mice under different food schedules.ResultsWe employed home cage feeders to first measure ad libitum food intake and then to dispense 20-mg pellets on a schedule mimicking that pattern. In both conditions, PER2::LUC bioluminescence peaked during the night as expected. Surprisingly, shifting the scheduled feeding by 12 h advanced peripheral clocks by only 0–3 h, much less than predicted from TRF protocols. To isolate the effects of feeding from the light-dark cycle, clock phase was then measured in mice acclimated to scheduled feeding over the course of 3 months in constant darkness. In these conditions, peripheral clock phases were better predicted by the rest-activity cycle than by the food schedule, contrary to expectation based on TRF studies. At the end of both experiments, mice were exposed to a modified TRF with food provided in eight equally sized meals over 12 h. In the light-dark cycle, this advanced the phase of the liver and kidney, though less so than in TRF with ad libitum access; in darkness, this entrained the liver and kidney but had little effect on the submandibular gland or the rest-activity cycle.ConclusionsThese data suggest that natural feeding patterns can only weakly affect circadian clocks. Instead, in normally feeding mice, the central pacemaker in the brain may set the phase of peripheral organs via pathways that are independent of feeding behavior.

DO ADJUSTING‐AMOUNT AND ADJUSTING‐DELAY PROCEDURES PRODUCE EQUIVALENT ESTIMATES OF SUBJECTIVE VALUE IN PIGEONS?

The current experiment examined whether adjusting-amount and adjusting-delay procedures provide equivalent measures of discounting. Pigeons' discounting on the two procedures was compared using a within-subject yoking technique in which the indifference point (number of pellets or time until reinforcement) obtained with one procedure determined the value of the corresponding variable in the yoked condition with the other procedure. Behavior on each procedure was well described by a hyperbolic discounting function. Results revealed no systematic differences in the degree of discounting as measured by the discounting rate parameter of the hyperbola in Experiment 1, which used 20-mg pellets. These results were replicated in Experiment 2 using smaller, 14-mg pellets, which potentially yield more precise measurement of indifference points on the adjusting-amount procedure. The finding that estimates of the k parameter in the hyperbolic discounting function obtained with one procedure did not differ systematically from estimates obtained from the same subjects with the other procedure represents strong support for the hypothesis that the same process underlies the discounting of delayed rewards on both adjusting-amount and adjusting-delay procedures.

C-Kit mutant mouse behavioral phenotype: altered meal patterns and CCK sensitivity but normal daily food intake and body weight.

The mouse W/Wv mutation of the c-Kit receptor causes extensive loss of gastrointestinal interstitial cells of Cajal and vagal intramuscular arrays (IMAs; one of the two putative mechanoreceptors in gastrointestinal smooth muscle). To characterize the behavioral phenotype of the c-Kit mouse and to evaluate the roles of these mechanoreceptors in controlling food intake, meal patterns and daily intakes of W/Wv mice and controls were examined using solid (20-mg pellets) and liquid (Isocal) maintenance diets. After the meal pattern experiments, CCK (0.5, 1, 2, 4, 8, and 16 microg/kg ip) was administered to examine the role of the interstitial cells and vagal IMA mechanoreceptors in relaying peripheral signals of satiety activated by CCK-A receptors, whereas the specificity of the response was assessed with the antagonist devazepide (300 microg/kg ip). On both diets, the W/Wv mice ate smaller meals for shorter durations, with a compensatory increase in meal number, resulting in daily intakes and body weights similar to the controls. After CCK injections, the mutant mice consistently suppressed intake more ( approximately 2x) in 30-min tests, regardless of the test diet (12.5% glucose, chow, pellets, and Isocal). The increased sensitivity of W/Wv mice to CCK reflected an increased potency of the hormone (c-Kit mouse ED50 = 2.4 microg/kg; control ED50 = 6.4 microg/kg) and a shift of the dose-response curve to the left. Devazepide blocked the CCK suppression of ingestion. These results indicate that the selective loss of the interstitial cells and IMAs disrupts short-term feeding of the W/Wv mice by inducing an earlier satiety, possibly by altering gastric accommodation and/or emptying, without affecting the long-term mechanisms controlling overall intake or body weight. The results also suggest that the reduction of interstitial cells and IMAs augments the sensitivity to or increases the efficiency of exogenous CCK.

Digoxin sensitivity in amyloid cardiomyopathy.

Digoxin (5 mg/ml) was added to 10-mg and 20-mg pellets of purified primary and secondary amyloid fibrils, a normal human liver and heart homogenate and a homogenate from the heart of a patient with amyloid cardiomyopathy who had not received digitalis. After centrifugation, the supernatants were recovered and assayed for digoxin concentrations. Aliquots from the sediments were studied for the presence of digoxin, using rabbits antidigoxin antiserum and an indirect immunofluorescent technique. The results showed that 0.11--0.13 ng/ml of digoxin bound per milligram of fibrils and could not be separated by repeated washings. Elution with citrate or changes in the pH of the buffer. Immunofluorescent studies demonstrated diffusely bright immunofluorescence with the fibril preparation and amyloid heart homogenate when reacted with digoxin and digoxin-specific antiserum. These studies demonstrate that isolated amyloid fibrils bind digoxin and suggest that this interaction may play some role in the sensitivity to digitalis that has been observed in some patients with amyloid cardiomyopathy.

Synergism of Diethylstilbestrol and Radiation in Mammary Carcinogenesis in Female F344 Rats2

One compressed 20-mg pellet containing cholesterol only or cholesterol mixed with 0.98, 1.6, 2.6, or 3.9 mg of diethylstilbestrol (DES) was implanted into each of 203 female F344 rats. Two days later, half the animals in each group were exposed to 150 R of X-rays, and the other half were sham irradiated. The rats were maintained until 350 days post implantation. Mortality increased with the higher doses of DES, with or without X-rays. DES at all dose levels, with or without X-rays, produced pituitary tumors and pyometritis. Only rats that received both DES and X-rays had mammary adenocarcinomas (AC). A synergistic AC response was found in the group that received 2.6 mg DES plus X-rays. Synergism was defined as a significantly greater incidence of rats with mammary neoplasia resulting from DES plus X-ray treatment when compared to the summed incidence from comparable individual treatments. For all other groups of rats that received both treatments, synergism was detected only when their data were combined. Synergism was not detected among rats that had fibroadenomas (FA). Both types of neoplasms were independent phenomena because no significant relationship was found between the incidences of FA and AC.

少數訓練試行事態における部分強化効果

In 2 experiments, 2 intertrial intervals (90sec or 24hr) and reinforcement schedules (continuous or partial) were combined factorially for 60 rats in straight alley type learning. One 320-mg pellet per reinforced trial was given in Exp. I, and sixteen 20-mg pellets in Exp. II. The rats received only 5 training and 20 extinction trials. A significant partial reinforcement effect (PRE) was obtained irrespectively of the length of intertrial interval or of the number of pellets. The data were not consistent with Amsel's hypothesis that the small-trial PRE was affected by the number of pellets given. Several implications of the present results were discussed in relation to Capaldi's stimulus-aftereffect hypothesis.

Learning to escape cues paired with reward reductions following single- or multiple-pellet rewards

In Experiment 1, three groups of rats were given 60 runway acquisition trials (6/day) to either one 500-mg pellet (Group 1L), 25 20-mg pellets (Group 25S), or one 20-mg pellet (Group IS). Rate of approach to asymptote was faster for Group 25S than for Group 1L, and at asymptote, they ran faster than Group IS. All groups then received one 20-mg pellet for 30 trials. Group 25S showed a greater depression effect than did Group 1L. The acquisition results were replicated in Experiment 2, and, during a third phase in which Ss were given hurdle-jump training, both shifted groups jumped faster than Group IS, but Group 25S jumped the fastest. It was concluded that greater amounts of frustration are elicited when both reward magnitude and number of pellets are reduced than when only reward magnitude is reduced.