Nucleus accumbens GLP-1 receptors influence meal size and palatability

Recent evidence suggests that the glucagon-like peptide-1 (GLP-1) neuronal projection to the nucleus accumbens core (NAcC) contributes to food intake control. To investigate the role of endogenous stimulation of GLP-1 receptors (GLP-1R) in NAcC, we examined the effects of the GLP-1R antagonist exendin-(9–39) (Ex9) on meal pattern and microstructure of ingestive behavior in rats. Intra-NAcC Ex9 treatment selectively increased meal size relative to vehicle in rats consuming 0.25 M sucrose solution or sweetened condensed milk. Microstructural analysis revealed effects of NAcC Ex9 on initial lick rate and the size and duration of licking bursts in rats consuming 0.1 or 0.25 M sucrose, suggesting that blockade of NAcC GLP-1R increases palatability. Because NAcC Ex9 did not affect licking for nonnutritive saccharin (0.1%), we suggest that the presence of nutrients in the gut may be required for endogenous stimulation of NAcC GLP-1R. Consistent with this, we also found that the meal size-suppressive effects of intragastric nutrient infusion were attenuated by NAcC delivery of Ex9 at a dose that had no effect when delivered alone. Analysis of licking patterns revealed that NAcC Ex9 did not reverse intragastric nutrient-induced suppression of burst number but rather blunted the effect of nutrient infusion on meal size primarily by increasing the size and duration of licking bursts. Together, our results suggest that NAcC Ex9 influences taste evaluation. We conclude that GLP-1 released in NAcC in response to gastrointestinal nutrients reduces the hedonic value of food.

Ghrelin increases the motivation to eat, but does not alter food palatability

Homeostatic eating cannot explain overconsumption of food and pathological weight gain. A more likely factor promoting excessive eating is food reward and its representation in the central nervous system (CNS). The anorectic hormones leptin and insulin reduce food reward and inhibit related CNS reward pathways. Conversely, the orexigenic gastrointestinal hormone ghrelin activates both homeostatic and reward-related neurocircuits. The current studies were conducted to identify in rats the effects of intracerebroventricular ghrelin infusions on two distinct aspects of food reward: hedonic valuation (i.e., “liking”) and the motivation to self-administer (i.e., “wanting”) food. To assess hedonic valuation of liquid food, lick motor patterns were recorded using lickometry. Although ghrelin administration increased energy intake, it did not alter the avidity of licking (initial lick rates or lick-cluster size). Several positive-control conditions ruled out lick-rate ceiling effects. Similarly, when the liquid diet was hedonically devalued with quinine supplementation, ghrelin failed to reverse the quinine-associated reduction of energy intake and avidity of licking. The effects of ghrelin on rats' motivation to eat were assessed using lever pressing to self-administer food in a progressive-ratio paradigm. Ghrelin markedly increased motivation to eat, to levels comparable to or greater than those seen following 24 h of food deprivation. Pretreatment with the dopamine D1 receptor antagonist SCH-23390 eliminated ghrelin-induced increases in lever pressing, without compromising generalized licking motor control, indicating a role for D1 signaling in ghrelin's motivational feeding effects. These results indicate that ghrelin increases the motivation to eat via D1 receptor-dependent mechanisms, without affecting perceived food palatability.

Anatomical dissociation of melanocortin receptor agonist effects on taste- and gut-sensitive feeding processes

Injections of the melanocortin 3/4 receptor (MCR) agonist melanotan II (MTII) to a variety of brain structures produces anorexia, suggesting distributed brain MCR control of food intake. We performed a detailed analysis of feeding behavior (licking microstructure analysis) after a range of MTII doses (0.005 nM to 1 nM) was targeted to the forebrain (third ventricle, 3V) or hindbrain (fourth ventricle, 4V) regions. MTII (0.1 nM and 1 nM) delivered to the 3V or 4V significantly reduced 0.8 M sucrose intake. The anorexia was mediated by reductions in the number of licking bursts in the meal, intrameal ingestion rate, and meal duration; these measures have been associated with postingestive feedback inhibition of feeding. Anorexia after 3V but not 4V MTII injection was also associated with a reduced rate of licking in the first minute (initial lick rate) and reduced mean duration of licking bursts; these measures have been associated with taste evaluation. MTII effects on taste evaluation were further explored: In experiment 2, 3V MTII (1 nM) significantly reduced intake of noncaloric 4 mM saccharin and 0.1 M and 1 M sucrose solutions, but not water. The anorexia was again associated with reduced number of licking bursts, ingestion rate, meal duration, initial lick rate, and mean burst duration. In experiments 3 and 4, brief access (20 s) licking responses for sweet sucrose (0.015 M to 0.25 M) and bitter quinine hydrochloride (0.01 mM to 1 mM) solutions were evaluated. Licking responses for sucrose were suppressed, whereas those for quinine solutions were increased after 3V MTII, but not after 4V MTII injections (0.1 nM and 1 nM). The results suggest that multiple brain MCR sites influence sensitivity to visceral feedback, whereas forebrain MCR stimulation is necessary to influence taste responsiveness, possibly through attenuation of the perceived intensity of taste stimuli.

Independent ingestion and microstructure of feeding patterns in infant rats lacking CCK-1 receptors

Otsuka Long-Evans Tokushima fatty (OLETF) rats are a strain of Long-Evans Tokushima Otsuka (LETO) rats that do not express CCK-1 receptors, developing in adulthood, hyperphagia, obesity, and non-insulin-dependent diabetes mellitus (NIDDM). We examined weight gain and meal patterns during a 30-min independent ingestion test on postnatal days 2–4 and again on days 9–11 in OLETF and LETO rat pups. OLETF pups were significantly heavier compared with their LETO controls at both ages, and they consumed significantly more of the sweet milk diet. The difference in intake can be attributed to a significant increase in meal size and duration. Number of clusters and bursts of licking within a meal were greater in OLETF rat pups, with no difference between strains in burst and cluster size. Interlick interval (ILI) was not significantly different between OLETF and LETO pups. This measure decreased on days 9–11 compared with days 2–4 in both strains. Latency to start feeding was significantly shorter on days 2–4 in OLETF vs. LETO pups, but this difference disappeared at the second test at the older age. Two- to four-day-old OLETF pups consumed a larger volume of milk during the first minute of feeding, and their initial lick rate and decay of lick rate were significantly larger compared with their LETO controls. Lack of CCK-1 receptors, or other OLETF-related abnormalities, therefore, resulted in a satiation deficit, leading to increased meal size, hyperphagia, and increased weight gain as early as 2–4 postnatal days.

Behavioral analysis of anorexia produced by hindbrain injections of AMPA receptor antagonist NBQX in rats

The caudal brain stem integrates short-term feedback signals from the oral cavity and the food-handling abdominal viscera, as well as long-term homeostatic, cognitive, and emotional signals from the forebrain, to control ingestive behavior. Glutamate, acting on various receptor subtypes, plays a prominent role in this integrative process. Fourth ventricular injection of the α-amino-3-hydroxy-5-methyl-4-isoxazolepropionate (AMPA)/kainate receptor blocker 1,2,3,4-tetrahydro-6-nitro-2,3-dioxobenzo[ f]quinoxaline-7-sulfonamide (NBQX, 0.5–5 nmol/3 μl) dose dependently suppressed intake of 15% sucrose in food-deprived and non-food-deprived rats compared with saline injection. Two consecutive paired NBQX injections (5 nmol) into the fourth ventricle did not produce conditioned taste aversion to saccharin, but LiCl did. Intraburst lick rate and lick efficiency were not affected, but burst size and number and initial lick rate were significantly decreased by NBQX. Local injection of NBQX (2 nmol) into and near the nucleus tractus solitarius also suppressed sucrose intake. These results suggest a general role for non- N-methyl-d-aspartate receptors in the transmission of positive (feedforward) signals, but do not identify the exact processing step involved, such as taste input, sensory-motor processing, or descending facilitation. More localized injections and response measures will be necessary.

Intracerebroventricular CART peptide reduces rat ingestive behavior and alters licking microstructure

Intracerebroventricular administration of cocaine- and amphetamine-regulated transcript (CART) peptides reduces food intake and increases c-Fos in brain areas involved in the control of feeding. To discern behavioral mechanisms through which CART alters the microstructure of feeding, we injected CART-(55–102) (0.1, 0.5, 1, 2 μg, and saline controls) into the lateral ventricle of male Sprague-Dawley rats 5 min before dark onset and, using lickometers, monitored the ingestion of an Ensure liquid diet for the first 6 h of dark. At a threshold dose of 1 μg, CART dose dependently 1) decreased intake of Ensure in licks; 2) decreased meal size, but did not alter meal duration or number; 3) reduced initial lick rate of meals; and 4) significantly reduced burst number, licks/burst, and licks/cluster. CART dose dependently increased interlick interval (0.5 μg threshold, 192 ± 4 vs. 183 ± 3 ms, control; 1 μg: 201 ± 1 ms; 2 μg: 214 ± 6 ms). These data suggest that altered oral motor function, and possibly palatability perception, may be fundamental to the anorexigenic action of CART.

Amiloride-sensitive signals and NaCl preference and appetite: a lick-rate analysis

Rats prefer hypotonic and isotonic NaCl solutions to water in long-access drinking paradigms. To focus on the role of taste signals in NaCl preference, licking patterns of rats with 30-s exposure to NaCl solutions (0–0.5 M) were examined when they were either water deprived, sodium depleted, or not deprived (NaCl mixed in dilute sucrose). In all three conditions, rats displayed a preference for NaCl. The addition of 100 μM amiloride, a sodium channel blocker, to NaCl did not change rats' licking when they were sodium replete but dramatically reduced licking when they were deplete. Transection of the chorda tympani (CT) nerve, an afferent pathway for amiloride-sensitive Na+ signals, had no effect on NaCl preference in nondeprived rats and only a modest effect on those that were Na+ deplete. Amiloride was found to exert significant suppression of NaCl intake in Na+-depleted rats with transection of the CT, supporting the existence of other afferent pathways for transmission of amiloride-sensitive Na+signalling. Together, these studies argue for the involvement of different neural signalling mechanisms in NaCl preference in the presence and absence of explicit Na+ need.

Effect of hepatic glucose infusion on glucose intake and licking microstructure in deprived and nondeprived rats

The effects of hepatic-portal glucose or saline infusions on intake and the temporal distribution of licking (lick microstructure) were evaluated in nondeprived and in 20.5-h food-deprived rats. Rats received portal infusions of isotonic glucose or saline (0.1 ml/min) for 2 h before and then throughout a 90-min period of access to a spout that delivered 12.5% glucose. Overall, a significant treatment-related intake suppression was obtained in nondeprived but not in deprived groups. For both groups, however, there was a significant positive linear relationship between the amount individual rats consumed under the saline (baseline) infusion condition and the extent to which portal glucose infusion suppressed intake. The linear fit for the deprived group was similar in slope, but right shifted, relative to the best fit for the nondeprived group. The individual-subject and group differences in response to portal glucose infusion are discussed in relation to the inconsistent literature on this treatment’s short-term intake effects. We focused analysis of the licking pattern on those rats for which a prominent portal glucose infusion effect was obtained (i.e., nondeprived rats with higher than average baseline intakes). Features of the lick pattern associated with taste evaluation (1st min lick rate; lick burst duration) were not significantly affected by portal glucose infusion. Rather, the minute-by-minute rate of ingestion under glucose infusion declined more rapidly than under baseline tests, indicating that portal glucose infusion enhanced the inhibitory influence of the accumulating postingestive load.