Lick Rate Research Articles

The efficacy of capsaicin as an equine repellent for chewing wood

Capsaicin, a component of chili peppers, is a natural repellent for many mammals because of it being an irritant to the nasal and oral areas. We tested whether topical application of capsaicin in a commercially available product caused aversion to licking and chewing of wood by horses and hence might potentially prevent crib biting. Ten non–wood-chewing horses underwent 3 sequential trials involving the presentation of different treatments applied to a clean piece of wood (wooden block). Initially horses were exposed to molasses only, followed by equal proportions of molasses and the capsaicin product (Equi-Stop), and then a return to molasses only. The addition of capsaicin to molasses caused a significant reduction in the frequency of licking or chewing of a standardized wooden block and was associated with significant increases in behaviors that may be associated with equine irritation, including rubbing and head shaking, plus the nasal investigative behavior of flehmen response. The combination of both the reduction of licking or chewing of the wooden block and the increase in irritation and nasal investigation behaviors suggests that capsaicin may be an effective repellent for horses chewing wood. The significantly lower licking or chewing rates of wooden blocks coated with molasses only at the end of the trial sequence compared to that at the start suggests a learned aversion after exposure to capsaicin at least in some horses. This capsaicin-based product has the potential as a management tool for reducing the incidence of wood chewing and possibly crib biting in horses.

Oxytocin decreases sweet taste sensitivity in mice

Oxytocin (OXT) suppresses food intake and lack of OXT leads to overconsumption of sucrose. Taste bud cells were recently discovered to express OXT-receptor. In the present study we tested whether administering OXT to wild-type mice affects their licking behavior for tastants in a paradigm designed to be sensitive to taste perception. We injected C57BL/6J mice intraperitoneally (i.p.) with 10mg/kg OXT and assayed their brief-access lick responses, motivated by water deprivation, to NaCl (300mM), citric acid (20mM), quinine (0.3mM), saccharin (10mM), and a mix of MSG and IMP (100mM and 0.5mM respectively). OXT had no effect on licking for NaCl, citric acid, or quinine. A possible effect of OXT on saccharin and MSG+IMP was difficult to interpret due to unexpectedly low lick rates to water (the vehicle for all taste solutions), likely caused by the use of a high OXT dose that suppressed licking and other behaviors. A subsequent experiment focused on another preferred tastant, sucrose, and employed a much lower OXT dose (0.1mg/kg). This modification, based on our measurements of plasma OXT following i.p. injection, permitted us to elevate plasma [OXT] sufficiently to preferentially activate taste bud cells. OXT at this low dose significantly reduced licking responses to 0.3M sucrose, and overall shifted the sucrose concentration — behavioral response curves rightward (mean EC50saline=0.362M vs. EC50OXT=0.466M). Males did not differ from females under any condition in this study. We propose that circulating oxytocin is another factor that modulates taste-based behavior.

Examination of the perception of sweet- and bitter-like taste qualities in sucralose preferring and avoiding rats

Sucralose avoiding rats detect a bitter-like taste quality in concentrations of sucralose that are strongly preferred over water by sucralose preferring rats. Here, we investigated whether sucralose preferrers (SP) also detect a bitter-like quality in sucralose that may be masked by an increased perception of sucralose's sweet-like quality. A microstructural analysis of sucralose intake revealed that, at concentrations they avoided in preference tests, sucralose avoiders (SA) consumed smaller and fewer bouts of sucralose than SP. Interestingly, the concentration-dependent increase in sucralose preference in SP was not associated with larger bouts or increased lick rate, two measures that are expected to increase with increasing perceived sweetness. This suggests that SP can detect an aversive quality in sucralose, but this perception of a presumably bitter-like quality may be masked by increased salience of a sweet-like quality that sustains high levels of intake in SP. Further evidence for increased sweet-taste perception in SP, relative to SA, was obtained in a second study in which SP consumed more of a palatable sweet-milk diet than SA. These are the first data to suggest that SP are not blind to the bitter-like quality in sucralose, and that there may be differences in sweet-taste perception between SP and SA.

A microstructural analysis of schedule-induced polydipsia reveals incentive-induced hyperactivity in an animal model of ADHD

Recent research has suggested that frequent short bursts of activity characterize hyperactivity associated with attention deficit hyperactivity disorder (ADHD). This study determined whether such pattern is also visible in schedule-induced polydipsia (SIP) in the spontaneously hypertensive rat (SHR), an animal model of ADHD. Male SHR, Wistar Kyoto (WKY) and Wistar rats were exposed to 40 sessions of SIP using a multiple fixed-time (FT) schedule of food delivery with FT 30-s and FT 90-s components. Stable performance was analyzed to determine the extent to which SIP-associated drinking is organized in bouts. The Bi-Exponential Refractory Model (BERM) of free-operant performance was applied to schedule-induced licks. A model comparison analysis supported BERM as a description of SIP episodes: licks were not produced at a constant rate but organized into bouts within drinking episodes. FT 30-s induced similar overall licking rates, latencies to first licks and episode durations across strains; FT 90-s induced longer episode durations in SHRs and reduced licking rate in WKY and Wistar rats to nearly baseline levels. Across schedules, SHRs made more and shorter bouts when compared to the other strains. These results suggest an incentive-induced hyperactivity in SHR that has been observed in operant behaviour and in children with ADHD.

Salty taste deficits in CALHM1 knockout mice.

Genetic ablation of calcium homeostasis modulator 1 (CALHM1), which releases adenosine triphosphate from Type 2 taste cells, severely compromises the behavioral and electrophysiological responses to tastes detected by G protein-coupled receptors, such as sweet and bitter. However, the contribution of CALHM1 to salty taste perception is less clear. Here, we evaluated several salty taste-related phenotypes of CALHM1 knockout (KO) mice and their wild-type (WT) controls: 1) In a conditioned aversion test, CALHM1 WT and KO mice had similar NaCl avoidance thresholds. 2) In two-bottle choice tests, CALHM1 WT mice showed the classic inverted U-shaped NaCl concentration-preference function but CALHM1 KO mice had a blunted peak response. 3) In brief-access tests, CALHM1 KO mice showed less avoidance than did WT mice of high concentrations of NaCl, KCl, NH(4)Cl, and sodium lactate (NaLac). Amiloride further ameliorated the NaCl avoidance of CALHM1 KO mice, so that lick rates to a mixture of 1000 mM NaCl + 10 µM amiloride were statistically indistinguishable from those to water. 4) Relative to WT mice, CALHM1 KO mice had reduced chorda tympani nerve activity elicited by oral application of NaCl, NaLac, and sucrose but normal responses to HCl and NH(4)Cl. Chorda tympani responses to NaCl and NaLac were amiloride sensitive in WT but not KO mice. These results reinforce others demonstrating that multiple transduction pathways make complex, concentration-dependent contributions to salty taste perception. One of these pathways depends on CALHM1 to detect hypertonic NaCl in the mouth and signal the aversive taste of concentrated salt.

Behavioral palatability of dietary fatty acids correlates with the intracellular calcium ion levels induced by the fatty acids in GPR120-expressing cells.

We recently reported that G-protein-coupled receptor 120 (GPR120) is expressed on taste buds, and that rodents showed preference for long-chain fatty acids (LCFA) at a low concentration. We also showed that the LCFA (1% linoleic acid) increased the extracellular dopamine (DA) level in the nucleus accumbens (NAc), which participates in reward behavior. However, the mechanism underlying the involvement of the GPR120-agonistic activity of LCFA in the palatability of dietary fat remains elusive. Therefore, we examined the association between the GPR120-agonistic activity and palatability of LCFA. First, we measured Ca(2+) signaling in HEK293 cells stably expressing GPR120 under stimulation by various LCFAs. We then assessed the palatability of the various LCFAs by testing the licking behavior in mice and measured the changes in the NAc-DA level by in vivo microdialysis. Consequently, 14- to 22-carbon unsaturated LCFAs showed strong GPR120-agonistic activity. Additionally, mice displayed high licking response to unsaturated 16- and 18-carbon LCFAs, and unsaturated 18-carbon LCFA significantly increased the DA level. The licking rate and the LCFA-dependent increase in DA level also correlated well with the GPR120- agonistic activity. These findings demonstrate that chemoreception of LCFA by GPR120 is involved in the recognition and palatability of dietary fat.

Combined effects of food deprivation and food frequency on the amount and temporal distribution of schedule‐induced drinking

Under intermittent food schedules animals develop temporally organized behaviors throughout interfood intervals, with behaviors early in the intervals (interim) normally occurring in excess. Schedule-induced drinking (a prototype of interim, adjunctive behavior) is related to food deprivation and food frequency. This study investigated the interactions that resulted from combining different food-deprivation levels (70%, 80% or 90% free-feeding weights) with different food-occurrence frequencies (15-, 30- or 60-s interfood intervals) in a within-subjects design. Increases in food deprivation and food frequency generally led to increased licking, with greater differences due to food deprivation as interfood intervals became shorter. Distributions of licking were modestly shifted to later in the interfood interval as interfood intervals lengthened, a result that was most marked under 90% food deprivation, which also resulted in flatter distributions. It would therefore appear that food deprivation modulates the licking rate and the distribution of licking in different ways. Effects of food deprivation and food frequency are adequately explained by a theory of adjunctive behavior based on delayed food reinforcement, in contrast to alternative hypotheses.

Experience with Sugar Modifies Behavioral but not Taste-Evoked Medullary Responses to Sweeteners in Mice

Dietary exposure to sugars increases the preference for and intake of sugar solutions in mice. We used brief-access lick tests and multiunit electrophysiological recordings from the nucleus of the solitary tract (NST) to investigate the role of taste in diet-induced changes in sucrose responsiveness. We exposed C57BL/6J (B6) and 129X1/SvJ (129) mice to either a sucrose diet (chow, water, and a 500mM sucrose solution) or a control diet (chow and water) for 3 days. In B6 mice, exposure to the sucrose diet decreased the appetitive response (i.e., number of trials initiated) but had no effect on the consummatory response (i.e., rate of licking) to 500mM sucrose and 20mM saccharin. In 129 mice, exposure to the sucrose diet increased the appetitive response but had no effect on the consummatory response to the sweetener solutions. In the NST recordings, the B6 mice exhibited larger multiunit responses to sweeteners than 129 mice, but there was no effect of the sucrose diet in either strain. Our results indicate that sucrose exposure alters the appetitive response of B6 and 129 mice to sweeteners in diametrically opposed ways and that these changes are mediated by structures in the gustatory neuraxis above the NST (e.g., ventral forebrain).

Quality of maternal and paternal care predicts later stress reactivity in the cooperatively-breeding marmoset (Callithrix geoffroyi)

Variation in the early postnatal social environment can have lasting effects on hypothalamic-pituitary-adrenal (HPA) axis stress responses. Both rats and macaque monkeys subjected to low quality or abusive maternal care during the early postnatal period have more pronounced HPA responses to environmental stressors throughout development and into adulthood compared to animals reared in higher quality early maternal environments. However, little is known about the relative contributions to HPA stress response styles in developing offspring in species in which offspring care is routinely provided by group members other than the mother, such as in cooperatively breeding mammals. Marmoset monkeys exhibit cooperative offspring rearing, with fathers and older siblings providing care in addition to that provided by the mother. We evaluated the effects of early maternal, paternal, and older sibling care on HPA responses to social separation across development in captive white-faced marmoset offspring (Callithrix geoffroyi). We monitored offspring care by mothers, fathers, and older siblings in marmosets for the first 60 days of life. Later in development, each marmoset experienced three standardized social separation/novelty exposure stressors at 6, 12, and 18 months of age. During separation, we collected urine samples and analyzed them via enzyme immunoassay for cortisol levels. Infants that received higher rates of rejections from the entire family group showed higher cortisol responses to social separation. This relationship was found when mothers, fathers, and older siblings, were analyzed separately as well. No differences in cortisol responses were found between offspring that received high and low rates of carrying or high and low rates of licking and grooming by any group member. In the cooperatively breeding marmoset, early social cues from multiple classes of caregivers may influence HPA stress responses throughout the lifespan.

A High Throughput In Vivo Assay for Taste Quality and Palatability

Taste quality and palatability are two of the most important properties measured in the evaluation of taste stimuli. Human panels can report both aspects, but are of limited experimental flexibility and throughput capacity. Relatively efficient animal models for taste evaluation have been developed, but each of them is designed to measure either taste quality or palatability as independent experimental endpoints. We present here a new apparatus and method for high throughput quantification of both taste quality and palatability using rats in an operant taste discrimination paradigm. Cohorts of four rats were trained in a modified operant chamber to sample taste stimuli by licking solutions from a 96-well plate that moved in a randomized pattern beneath the chamber floor. As a rat’s tongue entered the well it disrupted a laser beam projecting across the top of the 96-well plate, consequently producing two retractable levers that operated a pellet dispenser. The taste of sucrose was associated with food reinforcement by presses on a sucrose-designated lever, whereas the taste of water and other basic tastes were associated with the alternative lever. Each disruption of the laser was counted as a lick. Using this procedure, rats were trained to discriminate 100 mM sucrose from water, quinine, citric acid, and NaCl with 90-100% accuracy. Palatability was determined by the number of licks per trial and, due to intermediate rates of licking for water, was quantifiable along the entire spectrum of appetitiveness to aversiveness. All 96 samples were evaluated within 90 minute test sessions with no evidence of desensitization or fatigue. The technology is capable of generating multiple concentration–response functions within a single session, is suitable for in vivo primary screening of tastant libraries, and potentially can be used to evaluate stimuli for any taste system.

The Fine Temporal Structure of the Rat Licking Pattern: What Causes the Variabiliy in the Interlick Intervals and How is it Affected by the Drinking Solution?

Licking is a repetitive behavior controlled by a central pattern generator. Even though interlick intervals (ILIs) within bursts of licks are considered fairly regular, the conditions that affect their variability are unknown. We analyzed the licking pattern in rats that licked water, 10% sucrose solution, or 10% ethanol solution, in 90-min recording sessions after 4h of water deprivation. The histograms of ILIs indicate that licking typically occurred at a preferred ILI of about 130-140ms with evidence of bimodal or multimodal distributions due to occasional licking failures. We found that the longer the pause between bursts of licks, the shorter was the first ILI of the burst. When bursts of licks were preceded by a pause >4 s, the ILI was the shortest (~110ms) at the beginning of the burst, and then it increased rapidly in the first few licks and slowly in subsequent licks. Interestingly, the first ILI of a burst of licks was not significantly different when licking any of the 3 solutions, but subsequent licks exhibited a temporal pattern characteristic of each solution. The rapid deceleration in intraburst licking rate was due to an increase from ~27ms to ~56ms in the tongue-spout contact duration while the intercontact interval was only slightly changed (80-90ms). Therefore, the contact duration seems to be the major factor that increases the variability in the ILIs and could be another means for the rat to adjust the amount of fluid ingested in each individual lick.

Reduced palatability in pain-induced conditioned taste aversions

The current study investigated whether internal pain-inducing agents can modulate palatability of a tastant in the same way as illness-inducing agents (e.g., lithium chloride). Similar to traditional conditioned taste aversion (CTA) experiments, during conditioning the rats were exposed to a saccharin solution followed by intraperitoneal injections of either gallamine (Experiment 1) or hypertonic sodium chloride (NaCl; Experiments 1 and 2). In addition to the total amount consumed, the time of each lick was recorded for lick pattern analysis. The results showed that both gallamine and hypertonic NaCl caused suppression in saccharin intake. Importantly, both lick cluster size and initial lick rate (the measures of taste palatability) were reduced as well. This pattern of results suggests that these pain-inducing agents reduce the hedonic value of the associated tastant and thus CTA is acquired. The current finding serves as evidence supporting the view that CTA is a broadly tuned mechanism that can be triggered by changes in internal body states following consummatory experience.

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.

Angiotensin II Modulates Salty and Sweet Taste Sensitivities

Understanding the mechanisms underlying gustatory detection of dietary sodium is important for the prevention and treatment of hypertension. Here, we show that Angiotensin II (AngII), a major mediator of body fluid and sodium homeostasis, modulates salty and sweet taste sensitivities, and that this modulation critically influences ingestive behaviors in mice. Gustatory nerve recording demonstrated that AngII suppressed amiloride-sensitive taste responses to NaCl. Surprisingly, AngII also enhanced nerve responses to sweeteners, but had no effect on responses to KCl, sour, bitter, or umami tastants. These effects of AngII on nerve responses were blocked by the angiotensin II type 1 receptor (AT1) antagonist CV11974. In behavioral tests, CV11974 treatment reduced the stimulated high licking rate to NaCl and sweeteners in water-restricted mice with elevated plasma AngII levels. In taste cells AT1 proteins were coexpressed with αENaC (epithelial sodium channel α-subunit, an amiloride-sensitive salt taste receptor) or T1r3 (a sweet taste receptor component). These results suggest that the taste organ is a peripheral target of AngII. The specific reduction of amiloride-sensitive salt taste sensitivity by AngII may contribute to increased sodium intake. Furthermore, AngII may contribute to increased energy intake by enhancing sweet responses. The linkage between salty and sweet preferences via AngII signaling may optimize sodium and calorie intakes.

Decreased consumption of sweet fluids in mu opioid receptor knockout mice: a microstructural analysis of licking behavior

Evidence suggests that the palatability of food (i.e., the hedonic impact produced by its sensory features) can promote feeding and may underlie compulsive eating, leading to obesity. Pharmacological studies implicate opioid transmission in the hedonic control of feeding, though these studies often rely on agents lacking specificity for particular opioid receptors. Here, we investigated the role of mu opioid receptors (MORs) specifically in determining hedonic responses to palatable sweet stimuli. In Experiment 1, licking microstructure when consuming sucrose solution (2 to 20%) was compared in MOR knockout and wildtype mice as a function of sucrose concentration and level of food deprivation. In Experiment 2, a similar examination was conducted using the palatable but calorie-free stimulus sucralose (0.001 to 1%), allowing study of licking behavior independent of homeostatic variables. In Experiment 1, MOR knockout mice exhibited several alterations in sucrose licking. Although wildtype mice exhibited a twofold increase in the burst length when food deprived, relative to the nondeprived test, this aspect of sucrose licking was generally insensitive to manipulations of food deprivation for MOR knockout mice. Furthermore, during concentration testing, their rate of sucrose licking was less than half that of wildtype mice. During sucralose testing (Experiment 2), MOR knockout mice licked at approximately half the wildtype rate, providing more direct evidence that MOR knockout mice were impaired in processing stimulus palatability. These results suggest that transmission through MORs mediates hedonic responses to palatable stimuli, and therefore likely contributes to normal and pathological eating.

Sensitivity to temporal reward structure in amygdala neurons.

SummaryThe time of reward and the temporal structure of reward occurrence fundamentally influence behavioral reinforcement and decision processes [1–11]. However, despite knowledge about timing in sensory and motor systems [12–17], we know little about temporal mechanisms of neuronal reward processing. In this experiment, visual stimuli predicted different instantaneous probabilities of reward occurrence that resulted in specific temporal reward structures. Licking behavior demonstrated that the animals had developed expectations for the time of reward that reflected the instantaneous reward probabilities. Neurons in the amygdala, a major component of the brain's reward system [18–29], showed two types of reward signal, both of which were sensitive to the expected time of reward. First, the time courses of anticipatory activity preceding reward delivery followed the specific instantaneous reward probabilities and thus paralleled the temporal reward structures. Second, the magnitudes of responses following reward delivery covaried with the instantaneous reward probabilities, reflecting the influence of temporal reward structures at the moment of reward delivery. In being sensitive to temporal reward structure, the reward signals of amygdala neurons reflected the temporally specific expectations of reward. The data demonstrate an active involvement of amygdala neurons in timing processes that are crucial for reward function.

The consequences of gustatory deafferentation on body mass and feeding patterns in the rat

The contribution of orosensory signals, especially taste, on body mass, and feeding and drinking patterns in the rat was examined. Gustatory deafferentation was produced by bilateral transection of the chorda tympani, glossopharyngeal, and greater superficial petrosal nerves. Total calories consumed from sweetened-milk diet and oil-chow mash by the nerve-transected rats significantly decreased relative to sham-operated controls, mostly attributable to decreases in bout number, but not size. Nevertheless, caloric intake steadily increased over the postsurgical observation period, but body mass remained below both presurgical baseline and control levels and did not significantly increase over this time. After the sweetened-milk diet/oil-chow mash phase, rats received a series of sucrose preference tests. Interestingly, the nerve-transected rats preferred sucrose, and intake did not differ from controls, likely due to the stimulus sharing some nontaste chemosensory properties with the sweetened-milk diet. The neurotomized rats initiated a greater number of sucrose-licking bouts that were smaller in size and slower in licking rate, compared with control rats, and, unlike in control rats, the latter two bout parameters did not vary across concentration. Thus, in the absence of gustatory neural input, body mass is more stable compared with the progressive trajectory of weight gain seen in intact rats, and caloric intake initially decreases but recovers. The consequences of gustatory neurotomy on processes that determine meal initiation (bout number) and meal termination (bout size) are not fixed and appear to be influenced by presurgical experience with food stimuli coupled with its nongustatory chemosensory properties.

Distinct neural ensembles in the rat gustatory cortex encode salt and water tastes

The gustatory cortex (GC) is important for perceiving the intensity of tastants but it remains unclear as to how single neurons in the region carry out this function. Previous studies have shown that taste-evoked activity from single neurons in GC can be correlated or anticorrelated with tastant concentration, yet whether one or both neural responses signal intensity is poorly characterized because animals from these studies were not trained to report the intensity of the concentration that they tasted. To address this issue, we designed a two-alternative forced choice (2-AFC) task in which freely licking rats distinguished among concentrations of NaCl and recorded from ensembles of neurons in the GC. We identified three neural ensembles that rapidly (<300 ms or ∼2 licks) processed NaCl concentration. For two ensembles, their NaCl evoked activity was anticorrelated with NaCl concentration but could be further distinguished by their response to water; in one ensemble, water evoked the greatest response while in the other ensemble the lowest tested NaCl concentration evoked the greatest response. However, the concentration sensitive activity from each of these ensembles did not show a strong association with the behaviour of the rat in the 2-AFC task, suggesting a lesser role for signalling tastant intensity. Conversely, for a third neural ensemble, its neural activity was well correlated with increases in NaCl concentration, and this relationship best matched the intensity perceived by the rat. These results suggest that this neuronal ensemble in GC whose activity monotonically increases with concentration plays an important role in signalling the intensity of the taste of NaCl.

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.

Genetic control of a central pattern generator: rhythmic oromotor movement in mice is controlled by a major locus near Atp1a2.

Fluid licking in mice is a rhythmic behavior that is controlled by a central pattern generator (CPG) located in a complex of brainstem nuclei. C57BL/6J (B6) and DBA/2J (D2) strains differ significantly in water-restricted licking, with a highly heritable difference in rates (h2≥0.62) and a corresponding 20% difference in interlick interval (mean ± SEM = 116.3±1 vs 95.4±1.1 ms). We systematically quantified motor output in these strains, their F1 hybrids, and a set of 64 BXD progeny strains. The mean primary interlick interval (MPI) varied continuously among progeny strains. We detected a significant quantitative trait locus (QTL) for a CPG controlling lick rate on Chr 1 (Lick1), and a suggestive locus on Chr 10 (Lick10). Linkage was verified by testing of B6.D2-1D congenic stock in which a segment of Chr 1 of the D2 strain was introgressed onto the B6 parent. The Lick1 interval on distal Chr 1 contains several strong candidate genes. One of these is a sodium/potassium pump subunit (Atp1a2) with widespread expression in astrocytes, as well as in a restricted population of neurons. Both this subunit and the entire Na+/K+-ATPase molecule have been implicated in rhythmogenesis for respiration and locomotion. Sequence variants in or near Apt1a2 strongly modulate expression of the cognate mRNA in multiple brain regions. This gene region has recently been sequenced exhaustively and we have cataloged over 300 non-coding and synonymous mutations segregating among BXD strains, one or more of which is likely to contribute to differences in central pattern generator tempo.