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T1R2-T1R3 is a heteromeric receptor that binds sugars, high potency sweeteners, and sweet taste blockers. In rodents, T1R2-T1R3 is largely responsible for transducing sweet taste perception. T1R2-T1R3 is also expressed in non-taste tissues, and a growing body of evidence suggests that it helps regulate glucose and lipid metabolism. It was previously shown that clofibric acid, a blood lipid-lowering drug, binds T1R2-T1R3 and inhibits its activity in vitro The purpose of this study was to determine whether clofibric acid inhibits sweetness perception in humans and is, therefore, a T1R2-T1R3 antagonist in vivo Fourteen participants rated the sweetness intensity of 4 sweeteners (sucrose, sucralose, Na cyclamate, acesulfame K) across a broad range of concentrations. Each sweetener was prepared in solution neat and in mixture with either clofibric acid or lactisole. Clofibric acid inhibited sweetness of every sweetener. Consistent with competitive binding, inhibition by clofibric acid was diminished with increasing sweetener concentration. This study provides in vivo evidence that the lipid-lowering drug clofibric acid inhibits sweetness perception and is, therefore, a T1R carbohydrate receptor inhibitor. Our results are consistent with previous in vitro findings. Given that T1R2-T1R3 may in part regulate glucose and lipid metabolism, future studies should investigate the metabolic effects of T1R inhibition., (© The Author 2016. Published by Oxford University Press. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

The perception of sweetness varies among individuals but the sources of this variation are not fully understood. Here, in a sample of 1,901 adolescent and young adults (53.8% female; 243 MZ and 452 DZ twin pairs, 511 unpaired individuals; mean age 16.2±2.8, range 12–26 years), we studied the variation in the perception of sweetness intensity of two monosaccharides and two high-potency sweeteners: glucose, fructose, neohesperidine dihydrochalcone (NHDC), and aspartame. Perceived intensity for all sweeteners decreased with age (2–5% per year) and increased with the history of otitis media (6–9%). Males rated aspartame slightly stronger than females (7%). We found similar heritabilities for sugars (glucose: h2=0.31, fructose: h2=0.34) and high-potency sweeteners (NHDC: h2=0.31, aspartame: h2=0.30); all were in the modest range. Multivariate modeling showed that a common genetic factor accounted for >75% of the genetic variance in the four sweeteners, suggesting that individual differences in perceived sweet intensity, which are partly due to genetic factors, may be attributed to a single set of genes. This study provided evidence of the shared genetic pathways between the perception of sugars and high-potency sweeteners.

Bitter taste perception influences human nutrition and health, and the genetic variation underlying this trait may play a role in disease susceptibility. To better understand the genetic architecture and patterns of phenotypic variability of bitter taste perception, we sequenced a 996 bp region, encompassing the coding exon of TAS2R16, a bitter taste receptor gene, in 595 individuals from 74 African populations and in 94 non-Africans from 11 populations. We also performed genotype-phenotype association analyses of threshold levels of sensitivity to salicin, a bitter anti-inflammatory compound, in 296 individuals from Central and East Africa. In addition, we characterized TAS2R16 mutants in vitro to investigate the effects of polymorphic loci identified at this locus on receptor function. Here, we report striking signatures of positive selection, including significant Fay and Wu's H statistics predominantly in East Africa, indicating strong local adaptation and greater genetic structure among African populations than expected under neutrality. Furthermore, we observed a "star-like" phylogeny for haplotypes with the derived allele at polymorphic site 516 associated with increased bitter taste perception that is consistent with a model of selection for "high-sensitivity" variation. In contrast, haplotypes carrying the "low-sensitivity" ancestral allele at site 516 showed evidence of strong purifying selection. We also demonstrated, for the first time, the functional effect of nonsynonymous variation at site 516 on salicin phenotypic variance in vivo in diverse Africans and showed that most other nonsynonymous substitutions have weak or no effect on cell surface expression in vitro, suggesting that one main polymorphism at TAS2R16 influences salicin recognition. Additionally, we detected geographic differences in levels of bitter taste perception in Africa not previously reported and infer an East African origin for high salicin sensitivity in human populations.

Cough is among the most common symptoms with which people present for medical attention, but evidence-based treatments remain limited. One issue compromising interpretation of clinical trials of cough preparations is that control formulations often are nearly as effective as those that contain active ingredients. This observation has caused some researchers to propose that one or more nominally inactive ingredients may have some physiological effects. For example, most liquid cough preparations are highly sweetened, and it has been suggested that sweet taste might modulate cough sensitivity. The fact that honey has been used for thousands of years as a cough remedy is consistent with this idea. However, empirical evidence for modulation of cough sensitivity by taste was lacking. Evidence is still sparse, but relevant experiments have now been published: rinsing the mouth with a sweet sucrose solution increased cough thresholds in a single-inhalation capsaicin challenge. Furthermore, rinsing the mouth with a bitter solution did not affect thresholds, an important demonstration of specificity. The underlying mechanisms of cough suppression by sweet taste are still unclear. However, extant data suggest that modulation of cough sensitivity by taste is a promising area for further investigation. Such work may lead to greater understanding of apparent placebo effects in clinical trials and provide empirical support for therapies based on stimulation of taste nerves.

The sense of taste is stimulated when nutrients or other chemical compounds activate specialized receptor cells within the oral cavity. Taste helps us decide what to eat and influences how efficiently we digest these foods. Human taste abilities have been shaped, in large part, by the ecological niches our evolutionary ancestors occupied and by the nutrients they sought. Early hominoids sought nutrition within a closed tropical forest environment, probably eating mostly fruit and leaves, and early hominids left this environment for the savannah and greatly expanded their dietary repertoire. They would have used their sense of taste to identify nutritious food items. The risks of making poor food selections when foraging not only entail wasted energy and metabolic harm from eating foods of low nutrient and energy content, but also the harmful and potentially lethal ingestion of toxins. The learned consequences of ingested foods may subsequently guide our future food choices. The evolved taste abilities of humans are still useful for the one billion humans living with very low food security by helping them identify nutrients. But for those who have easy access to tasty, energy-dense foods our sensitivities for sugary, salty and fatty foods have also helped cause over nutrition-related diseases, such as obesity and diabetes., (Copyright © 2013 Elsevier Ltd. All rights reserved.)

The NIH Toolbox for Assessment of Neurological and Behavioral Function (NIH Toolbox) is a set of brief measures for the assessment of cognitive function, emotional health, motor function, and sensory function for use in clinical trials and in epidemiologic and longitudinal studies. Gustatory perception is assessed as 1 of 6 areas of sensory function. A team of 11 scientists with expertise in taste perception selected 2 gustatory measures, 1 of which can be used in young pediatric populations. The measure selected for young pediatric populations assesses sucrose (sweet) taste preference and can also be used across the age span of 5 to 85 years. For adult populations, the selected measure is a regional test, which assesses variability in perceived intensity of quinine hydrochloride (bitter) when applied to the tongue tip as well as perceived with the whole mouth. The team also recommends the regional test for assessing other tastants, such as sodium chloride (salty). Validation studies have demonstrated that the measures modified for the NIH Toolbox correlate with more traditional assessments, and can identify known population differences in gustation.

Cough is a vital protective reflex that is triggered by both mechanical and chemical stimuli. The current experiments explored how chemosensory stimuli modulate this important reflex. Cough thresholds were measured using a single-inhalation capsaicin challenge. Experiment 1 examined the impact of sweet taste: Cough thresholds were measured after rinsing the mouth with a sucrose solution (sweet) or with water (control). Experiment 2 examined the impact of menthol: Cough thresholds were measured after inhaling headspace above a menthol solution (menthol vapor) or headspace above the mineral oil solvent (control). Experiment 3 examined the impact of rinsing the mouth with a (bitter) sucrose octaacetate solution. Rinsing with sucrose and inhaling menthol vapor significantly increased measured cough thresholds. Rinsing with sucrose octaacete caused a non-significant decrease in cough thresholds, an important demonstration of specificity. Decreases in cough reflex sensitivity from sucrose or menthol could help explain why cough syrups without pharmacologically active ingredients are often almost as effective as formulations with an added drug. Further, the results support the idea that adding menthol to cigarettes might make tobacco smoke more tolerable for beginning smokers, at least in part, by reducing the sensitivity of an important airway defense mechanism., (Copyright © 2012 Elsevier Ltd. All rights reserved.)

Although human bitter taste perception is hypothesized to be a dietary adaptation, little is known about genetic signatures of selection and patterns of bitter taste perception variability in ethnically diverse populations with different diets, particularly from Africa. To better understand the genetic basis and evolutionary history of bitter taste sensitivity, we sequenced a 2,975 bp region encompassing TAS2R38, a bitter taste receptor gene, in 611 Africans from 57 populations in West Central and East Africa with diverse subsistence patterns, as well as in a comparative sample of 132 non-Africans. We also examined the association between genetic variability at this locus and threshold levels of phenylthiocarbamide (PTC) bitterness in 463 Africans from the above populations to determine how variation influences bitter taste perception. Here, we report striking patterns of variation at TAS2R38, including a significant excess of novel rare nonsynonymous polymorphisms that recently arose only in Africa, high frequencies of haplotypes in Africa associated with intermediate bitter taste sensitivity, a remarkably similar frequency of common haplotypes across genetically and culturally distinct Africans, and an ancient coalescence time of common variation in global populations. Additionally, several of the rare nonsynonymous substitutions significantly modified levels of PTC bitter taste sensitivity in diverse Africans. While ancient balancing selection likely maintained common haplotype variation across global populations, we suggest that recent selection pressures may have also resulted in the unusually high level of rare nonsynonymous variants in Africa, implying a complex model of selection at the TAS2R38 locus in African populations. Furthermore, the distribution of common haplotypes in Africa is not correlated with diet, raising the possibility that common variation may be under selection due to their role in nondietary biological processes. In addition, our data indicate that novel rare mutations contribute to the phenotypic variance of PTC sensitivity, illustrating the influence of rare variation on a common trait, as well as the relatively recent evolution of functionally diverse alleles at this locus.

Psychophysical judgments often depend on stimulus context. For example, sugar solutions are judged sweeter when a tasteless fruity aroma has been added. Response context also matters; adding a fruity aroma to sugar increases the rated sweetness when only sweetness is considered but not when fruitiness is judged as well. The interaction between stimulus context and response context has been explored more extensively in taste-odor mixtures than in taste-taste mixtures. To address this issue, subjects in the current study rated the sourness of citric acid mixed with quinine (bitter), sodium chloride (salty), and cyclamate (sweet) (stimulus context). In one condition, subjects rated sourness alone. In another, subjects rated both sourness and the other salient quality (bitterness, saltiness, or sweetness) (response context). Sourness ratings were most sensitive to response context for sour-salty mixtures (i.e., ratings of sourness alone exceeded ratings of sourness made simultaneously with saltiness) and least sensitive to context for the sour-sweet mixtures (sourness ratings made under the 2 conditions were essentially identical). Response-context effects for the sour-bitter mixture were nominally intermediate. The magnitudes of these context effects were related to judgments of qualitative similarity between citric acid and the other stimuli, consistent with prior findings. These types of context effects are relevant to the study of taste-taste mixture interactions and should provide insight into the perceptual similarities among the taste qualities.

Background: The TAS1R1 and TAS1R3 G protein-coupled receptors are believed to function in combination as a heteromeric glutamate taste receptor in humans., Objective: We hypothesized that variations in the umami perception of glutamate would correlate with variations in the sequence of these 2 genes, if they contribute directly to umami taste., Design: In this study, we first characterized the general sensitivity to glutamate in a sample population of 242 subjects. We performed these experiments by sequencing the coding regions of the genomic TAS1R1 and TAS1R3 genes in a separate set of 87 individuals who were tested repeatedly with monopotassium glutamate (MPG) solutions. Last, we tested the role of the candidate umami taste receptor hTAS1R1-hTAS1R3 in a functional expression assay., Results: A subset of subjects displays extremes of sensitivity, and a battery of different psychophysical tests validated this observation. Statistical analysis showed that the rare T allele of single nucleotide polymorphism (SNP) R757C in TAS1R3 led to a doubling of umami ratings of 25 mmol MPG/L. Other suggestive SNPs of TAS1R3 include the A allele of A5T and the A allele of R247H, which both resulted in an approximate doubling of umami ratings of 200 mmol MPG/L. We confirmed the potential role of the human TAS1R1-TAS1R3 heteromer receptor in umami taste by recording responses, specifically to l-glutamate and inosine 5'-monophosphate (IMP) mixtures in a heterologous expression assay in HEK (human embryonic kidney) T cells., Conclusions: There is a reliable and valid variation in human umami taste of l-glutamate. Variations in perception of umami taste correlated with variations in the human TAS1R3 gene. The putative human taste receptor TAS1R1-TAS1R3 responds specifically to l-glutamate mixed with the ribonucleotide IMP. Thus, this receptor likely contributes to human umami taste perception.

Taste loss or alterations can seriously impact health and quality of life due to the resulting negative influence on eating habits and nutrition. Infection and inflammation are thought to be some of the most common causes of taste perception disorders. Supporting this view, neuro-immune interactions in the peripheral gustatory system have been identified, underlying the importance of this tissue in mucosal immunity, but we have little understanding of how these interactions influence taste perception directly or indirectly. This limited understanding is evident by the lack of even a basic knowledge of the resident immune cell populations in or near taste tissues. The present study characterized the distribution and population of the major immune cells and their subsets in healthy human anterior, lingual, fungiform papillae (FP) using immunohistochemistry. Dendritic cells (DCs) were the predominant innate immune cells in this tissue, including four subtypes: CD11c(+) DCs, DC-SIGN+ immature DCs, CD83(+) mature DCs, and CD1a(+) DCs (Langerhans cells). While most DCs were localized beneath the lamina propria and only moderately in the epithelium, CD1a(+) Langerhans cells were exclusively present within the epithelium and not in sub-strata. A small number of macrophages were observed. T lymphocytes were present throughout the FP with CD4(+) T cells more prevalent than CD8(+) T cells. Very few CD19(+) B lymphocytes were detected. The results show that DCs, macrophages, and T lymphocytes are the constitutive guardians of human FP taste tissue, with DCs and CD4 T cells being dominant, while B lymphocytes are rare under normal, healthy conditions. These observations provide a basic anatomical foundation for the immune response in the healthy human tongue as a basis for subsequent disease-related studies, but none of the present data indicate that the immune cell populations identified are, in fact, altered in individuals with abnormal taste perception.

To understand the functional similarities of fly and mammalian taste receptors, we used a top-down approach that first established the fly sweetener-response profile. We employed the fruit fly Drosophila melanogaster, an omnivorous human commensal, and determined its sensitivity to an extended set of stimuli that humans find sweet. Flies were tested with all sweeteners in 2 assays that measured their taste reactivity (proboscis extension assay) and their ingestive preferences (free roaming ingestion choice test). A total of 21 sweeteners, comprised of 11 high-potency sweeteners, 2 amino acids, 5 sugars, 2 sugar alcohols, and a sweet salt (PbCl2), were tested in both assays. We found that wild-type Drosophila responded appetitively to most high-potency sweeteners preferred by humans, even those not considered sweet by rodents or new world monkeys. The similarities in taste preferences for sweeteners suggest that frugivorous/omnivorous apes and flies have evolved promiscuous carbohydrate taste detectors with similar affinities for myriad high-potency sweeteners. Whether these perceptual parallels are the result of convergent evolution of saccharide receptor-binding mechanisms remains to be determined.

Seventy-four pairs of monozygotic (identical) twins and 35 pairs of dizygotic (fraternal) twins provided recognition thresholds (modified Harris-Kalmus test) for the sourness of citric acid and the saltiness of sodium chloride during the Twins Days Festival in Twinsburg, OH. Variance components (ACE) models were applied to the data: total variation = additive genetic (A) + common environment (C) + nonshared environment (E). The best-fit model of variation in recognition thresholds for sourness included an additive genetic factor, accounting for 53% of the variance, but no common environment component. This level of heritability, on par with that of sensitivity to the bitter compounds 6-n-propylthiouracil and phenylthiocarbamide, strongly suggests that genetic factors play a larger role than shared environment in determining individual differences in recognition thresholds for sourness. In contrast, the best-fit model for saltiness recognition included a common environment component, accounting for 22% of the variance in thresholds, but no additive component. This result suggests that environment plays a larger role than genetics in determining individual differences in recognition thresholds for saltiness.

The perceived bitterness intensity for bitter solutions of propylthiouracil (PROP), sucrose octa-acetate (SOA), quinine HCl and caffeine were examined in a genetically informative sample of 392 females and 313 males (mean age of 17.8 +/- 3.1 years), including 62 monozygotic and 131 dizygotic twin pairs and 237 sib pairs. Broad-sense heritabilities were estimated at 0.72, 0.28, 0.34, and 0.30 for PROP, SOA, quinine, and caffeine, respectively, for perceived intensity measures. Modeling showed 1) a group factor which explained a large amount of the genetic variation in SOA, quinine, and caffeine (22-28% phenotypic variation), 2) a factor responsible for all the genetic variation in PROP (72% phenotypic variation), which only accounted for 1% and 2% of the phenotypic variation in SOA and caffeine, respectively, and 3) a modest specific genetic factor for quinine (12% phenotypic variation). Unique environmental influences for all four compounds were due to a single factor responsible for 7-22% of phenotypic variation. The results suggest that the perception of PROP and the perception of SOA, quinine, and caffeine are influenced by two distinct sets of genes.

'Water-tastes' are gustatory after-impressions elicited by water following the removal of a chemical solution from the mouth, akin to colour after-images appearing on 'white' paper after fixation on coloured images. Unlike colour after-images, gustatory after-effects are poorly understood. One theory posits that 'water-tastes' are adaptation phenomena, in which adaptation to one taste solution causes the water presented subsequently to act as a taste stimulus. An alternative hypothesis is that removal of the stimulus upon rinsing generates a receptor-based, positive, off-response in taste-receptor cells, ultimately inducing a gustatory perception. Here we show that a sweet 'water-taste' is elicited when sweet-taste inhibitors are rinsed away. Responses of cultured cells expressing the human sweetener receptor directly parallel the psychophysical responses-water rinses remove the inhibitor from the heteromeric sweetener receptor TAS1R2-TAS1R3, which activates cells and results in the perception of strong sweetness from pure water. This 'rebound' activity occurs when equilibrium forces on the two-state allosteric sweet receptors result in their coordinated shift to the activated state upon being released from inhibition by rinsing.

The sense of taste provides humans with necessary information about the composition and quality of food. For humans, five basic tastes are readily distinguishable and include sweet, bitter, salty, sour, and savory (or umami). Although each of these qualities has individualized transduction pathways, sweet and umami tastes are believed to share a common receptor element, the T1R3 receptor subunit. The two G-protein-coupled heteromer receptors that comprise an umami stimulus receptor (T1R1-T1R3) and a sweetener receptor (T1R2-T1R3) constitute a potential link between these two qualities of perception. While the role of the individual monomers in each human heteromer has been examined in vitro, very little is known of the implication of this research for human perception, or specifically, how sweet and savory taste perceptions may be connected. Using a psychophysical approach, we demonstrate that lactisole, a potent sweetness inhibitor that binds in vitro to hT1R3, also inhibits a significant portion of the perception of umami taste from monosodium glutamate. Following the molecular logic put forward by Xu et al. (2004, Proc. Natl Acad. Sci. USA, 101, 14258-14263), our psychophysical data support the in vitro hypothesis that the shared T1R3 monomer moderates the activation of both T1R2 and T1R1 in humans and impairs suprathreshold perception, respectively, of sweetness and, to a lesser degree, umaminess in the presence of lactisole.

Individual differences in perception are ubiquitous within the chemical senses: taste, smell, and chemical somesthesis . A hypothesis of this fact states that polymorphisms in human sensory receptor genes could alter perception by coding for functionally distinct receptor types . We have previously reported evidence that sequence variants in a presumptive bitter receptor gene (hTAS2R38) correlate with differences in bitterness recognition of phenylthiocarbamide (PTC) . Here, we map individual psychogenomic pathways for bitter taste by testing people with a variety of psychophysical tasks and linking their individual perceptions of the compounds PTC and propylthiouracil (PROP) to the in vitro responses of their TAS2R38 receptor variants. Functional expression studies demonstrate that five different haplotypes from the hTAS2R38 gene code for operatively distinct receptors. The responses of the three haplotypes we also tested in vivo correlate strongly with individuals' psychophysical bitter sensitivities to a family of compounds. These data provide a direct molecular link between heritable variability in bitter taste perception to functional variations of a single G protein coupled receptor that responds to compounds such as PTC and PROP that contain the N-C=S moiety. The molecular mechanisms of perceived bitterness variability have therapeutic implications, such as helping patients to consume beneficial bitter-tasting compounds-for example, pharmaceuticals and selected phytochemicals.

We investigated the ability of zinc sulfate (5, 25, 50 mM) to inhibit the sweetness of 12 chemically diverse sweeteners, which were all intensity matched to 300 mM sucrose [800 mM glucose, 475 mM fructose, 3.25 mM aspartame, 3.5 mM saccharin, 12 mM sodium cyclamate, 14 mM acesulfame-K, 1.04 M sorbitol, 0.629 mM sucralose, 0.375 mM neohesperidin dihydrochalcone (NHDC), 1.5 mM stevioside and 0.0163 mM thaumatin]. Zinc sulfate inhibited the sweetness of most compounds in a concentration dependent manner, peaking with 80% inhibition by 50 mM. Curiously, zinc sulfate never inhibited the sweetness of Na-cyclamate. This suggests that Na-cyclamate may access a sweet taste mechanism that is different from the other sweeteners, which were inhibited uniformly (except thaumatin) at every concentration of zinc sulfate. We hypothesize that this set of compounds either accesses a single receptor or multiple receptors that are inhibited equally by zinc sulfate at each concentration.

In order to study potential mixture interactions among bitter compounds, selected sodium salts were added to five compounds presented either alone or as binary bitter-compound mixtures. Each compound was tested at a concentration that elicited 'weak' perceived bitterness. The bitter compounds were mixed at these concentrations to form a subset of possible binary mixtures. For comparison, the concentration of each solitary compound was doubled to measure bitterness inhibition at the higher intensity level elicited by the mixtures. The following sodium salts were tested for bitterness inhibition: 100 mM sodium chloride (salty), 100 mM sodium gluconate (salty), 100 and 20 mM monosodium glutamate (umami), and 50 mM adenosine monophosphate disodium salt (umami). Sucrose (sweet) was also employed as a bitterness suppressor. The sodium salts differentially suppressed the bitterness of compounds and their binary combinations. Although most bitter compounds were suppressed, the bitterness of tetralone was not suppressed, nor was the bitterness of the binary mixtures that contained it. In general, the percent suppression of binary mixtures of compounds was predicted by the average percent suppression of its two components. Within the constraints of the present study, the bitterness of mixtures was suppressed by sodium salts and sucrose independently, with few bitter interactions. This is consistent with observations that the bitter taste system integrates the bitterness of multi-compound solutions linearly.

Genetic approaches are rapidly yielding new information about our sense of taste. This information comes from both molecular studies of genes encoding taste receptors and other taste-signaling components, and from studies of inherited variation in taste abilities. Our understanding of bitter taste has advanced by combined information from discovery and study of the TAS2R family of taste receptor genes, hand in hand with genetic linkage and positional cloning studies, notably on the ability to taste phenylthiocarbamide (PTC). Sweet and umami tastes, mediated by TAS1R receptors, are becoming well-characterized at the molecular genetic level, and these taste classes are now targets for linkage, positional cloning, and genetic association strategies. Salty and sour tastes are still poorly characterized in genetic terms, and represent opportunities for the future.

Purpose: NaCl has proven to be an effective bitterness inhibitor, but the reason remains unclear. The purpose of this study was to examine the influence of a variety of cations and anions on the bitterness of selected oral pharmaceuticals and bitter taste stimuli: pseudoephedrine, ranitidine, acetaminophen, quinine, and urea., Method: Human psychophysical taste evaluation using a whole mouth exposure procedure was used., Results: The cations (all associated with the acetate anion) inhibited bitterness when mixed with pharmaceutical solutions to varying degrees. The sodium cation significantly (P < 0.003) inhibited bitterness of the pharmaceuticals more than the other cations. The anions (all associated with the sodium cation) also inhibited bitterness to varying degrees. With the exception of salicylate, the glutamate and adenosine monophosphate anions significantly (P < 0.001) inhibited bitterness of the pharmaceuticals more than the other anions. Also, there were several specific inhibitory interactions between ammonium, sodium and salicylate and certain pharmaceuticals., Conclusions: We conclude that sodium was the most successful cation and glutamate and AMP were the most successful anions at inhibiting bitterness. Structure forming and breaking properties of ions, as predicted by the Hofmeister series. and other physical-chemical ion properties failed to significantly predict bitterness inhibition.

Induction of olfactory sensitivity in humans was first illustrated when men and women who were initially unable to smell the volatile steroid androstenone (5alpha-androst-16-en-3-one) developed that ability after repeated, brief exposures. Because this finding has not been replicated with other compounds in humans, it has been assumed that olfactory induction is a narrowly constrained phenomenon, occurring only in individuals with specific anosmias, perhaps only to androstenone (compare ref. 2). Here we show that induction of enhanced olfactory sensitivity seems to be a more general phenomenon, with marked changes in olfactory acuity occurring during repeated test exposures to several odorants among people with average baseline sensitivity to these compounds. This increased sensitivity (averaging five orders of magnitude) was observed only among females of reproductive age. These observations provide convincing evidence that female olfactory acuity to a variety of odorants can vastly improve with repeated test exposures. They also suggest a sensory basis for the anecdotal observation of greater olfactory sensitivities among females and raise the possibility that the olfactory-induction process may be associated with female reproductive behaviors such as pair bonding and kin recognition.

A previous study investigating individuals' bitterness sensitivities found a close association among three compounds: L-tryptophan (L-trp), L-phenylalanine (L-phe) and urea (Delwiche et al., 2001, Percept. Psychophys. 63, 761-776). In the present experiment, psychophysical cross-adaptation and bitterness inhibition experiments were performed on these three compounds to determine whether the bitterness could be differentially affected by either technique. If the two experimental approaches failed to differentiate L-trp, L-phe and urea's bitterness, then we may infer they share peripheral physiological mechanisms involved in bitter taste. All compounds were intensity matched in each of 13 subjects, so the judgments of adaptation or bitterness inhibition would be based on equal initial magnitudes and, therefore, directly comparable. In the first experiment, cross-adaptation of bitterness between the amino acids was high (>80%) and reciprocal. Urea and quinine-HCl (control) did not cross-adapt with the amino acids symmetrically. In a second experiment, the sodium salts, NaCl and Na gluconate, did not differentially inhibit the bitterness of L-trp, L-phe and urea, but the control compound, MgSO(4), was differentially affected. The bitter inhibition experiment supports the hypothesis that L-trp, L-phe and urea share peripheral bitter taste mechanisms, while the adaptation experiment revealed subtle differences between urea and the amino acids indicating that urea and the amino acids activate only partially overlapping bitter taste mechanisms.

The human tongue is a relatively symmetrical anatomical structure and is generally assumed functionally equivalent on both sides. Experimental evaluation of this assumption is complicated by the fact that psychophysical measurements tend to vary considerably across testing sessions. To address functional laterality, we determined the detection thresholds of six right-handed and six left-handed subjects for Na saccharin, NaCl, citric acid and quinine HCl. Five pairs of interwoven, left and right unilateral thresholds were obtained for each taste stimulus in 12 subjects (n = 480 separate thresholds). In most cases mean sensitivity based on multiple measurements was found to be laterally symmetrical, however, we observed a few cases of lateral asymmetry of both general and compound-specific sensitivity. Threshold values were found to vary considerably across sessions, consistent with the test-retest variability previously reported for whole mouth thresholds. We conclude that taste threshold sensitivity is equivalent on the left and right anterior tongue for most individuals. Given the occasional exceptions to this rule, however, it is advisable to employ a counterbalanced design for any experimental or clinical testing protocol in which treatments are applied asymmetrically to the tongue.

Chronic rinsing with chlorhexidine, an oral-antiseptic, has been shown to decrease the saltiness of NaCl and the bitterness of quinine. The effect of acute chlorhexidine on taste has not been investigated. The purpose of the present study was to examine the effect of acute chlorhexidine rinses on taste intensity and quality of 11 stimuli representing sweet, salt, sour, bitter and savory. All stimuli were first matched for overall intensity so the effects of chlorhexidine would be directly comparable across compounds. As a control treatment, the bitter taste of chlorhexidine digluconate (0.12%) was matched in intensity to quinine HCl, which was found to cross-adapt the bitterness of chlorhexidine. Subjects participated in four experimental conditions: a pre-test, a quinine treatment, a chlorhexidine treatment, and a post-test condition, while rating total taste intensity and taste qualities in separate test sessions. Relative to the quinine treatment, chlorhexidine was found to decrease the salty taste of NaCl, KCl and NH4Cl, and not to significantly affect the tastes of sucrose, monosodium glutamate (MSG), citric acid, HCl and the taste of water. The bitter taste of urea, sucrose octa-acetate and quinine were suppressed after chlorhexidine rinses relative to water rinses, but were only marginally suppressed relative to quinine rinses. Potential mechanisms are discussed.

This paper reports a study of the oral and pharyngeal chemesthetic effects of the non-steroidal anti-inflammatory drug (NSAID) ibuprofen [2-(4-isobutylphenyl)propanoic acid], which pilot experiments had indicated produces an unusual sensory irritation of the throat. In experiment 1 subjects swallowed aqueous solutions of ibuprofen prepared with different buffering agents and gave ratings of irritation and taste in the mouth and throat. The results showed that ibuprofen irritates the throat much more than the mouth, and that its quality in the throat is characterized primarily as sting/prick, itch and tickle (often leading to cough). Based upon the results obtained with the different buffering agents, we hypothesized that the sting/prick/itch qualities of throat irritation were pH-dependent. Parametric manipulation of solution pH in experiment 2 confirmed this hypothesis. The same experiment revealed that, in contrast to other oral irritants (e.g. capsaicin and menthol), repeated stimulation caused neither sensitization nor desensitization of throat irritation. In the final experiment we found that ibuprofen's throat irritation could not be modulated by temperature, as it should be if stimulation occurred via capsaicin-sensitive receptors. We therefore conclude that ibuprofen has novel chemesthetic properties, which are not mediated by capsaicin-sensitive (vanilloid) receptors, and that a major component of the throat irritation it produces occurs via a pH-dependent receptor mechanism.

There have been very few investigations of the spatial properties of taste stimuli localized to specific areas of the oral cavity. This is surprising, since the spatial localization of taste sensations may contribute to the overall taste percept, much as do quality, intensity, and the temporal characteristics of tastes. The difficulty in eliminating the confounding factor of a tactile sensation may partially account for the paucity of such studies, since a gustatory stimulus cannot be presented as a liquid without a tactile component. As a step toward understanding the localizability of gustatory sensations, we designed a yoked stimulator and an experimental procedure to control for tactile cues. Lateral discrimination was evaluated at the tip of the tongue with four taste stimuli (sodium saccharin, sodium chloride, citric acid, and quinine hydrochloride) by presenting a taste and a blank solution simultaneously at two locations on the tongue. We found that subjects could lateralize all four taste stimuli in the absence of any discriminative tactile cues. Subjects' ability to lateralize varied as a psychometric function of the stimulus concentration. Detection thresholds, measured in a forced-choice two-interval staircase procedure with the same yoked stimulator that was used in the lateralization task, were always lower than lateralization thresholds, and both lateralization and detection thresholds were correlated within subjects. Subjects were unable to lateralize taste cues on a nongustatory surface under the upper lip at the highest tested concentrations, at which performance was 100% on a gustatory surface (dorsal anterior tongue). These results show that (1) taste compounds can be lateralized in the absence of any discriminative mechanical cue (but only on the gustatory epithelium) and (2) although the localization of a compound does not logically require conscious detection of the taste (cf. blind sight), subjects always detected a taste when they were able to lateralize.

Recent studies have shown that people can localize a punctate gustatory stimulus on the lingual epithelium in the absence of discriminative tactile cues. The present studies examined the human ability to localize taste sensations on the tongue and to use this information to remove selectively a target stimulus (a flavored, 1 cm(3) gelatin cube) from the mouth when presented with non-target distractors that vary in number and taste. Findings indicate that humans are capable of localizing and removing either an aversive or an appetitive gustatory target from a field of tactile distractors via taste sensations alone, although this ability diminishes as the number of distractors increases (implicating serial searches, rather than parallel). In addition, humans can localize and selectively remove a target taste in the presence of distractors of another distinct taste quality. Under these conditions performance is either unaffected or reduced, which indicates that contrast with the distinct taste of the distractors does not enhance performance. Humans also are capable of removing a nearly tasteless cube from a field of flavored distractors, but this is clearly a more difficult task, suggesting that 'tactile capture' of taste occurs for the tasteless target cube and interferes with the localization of taste. Finally, perceived suprathreshold stimulus intensity did not seem to be related to the ability to localize and remove a target stimulus via taste sensations and failed to account for variations in performance across individuals.

We investigated the ability of subjects to discriminate sugars with a whole-mouth forced-choice paradigm, in which a standard solution was compared with a test solution of varied concentration. Discrimination probabilities were U-shaped functions of test concentration: for 6 subjects and pairwise combinations of fructose, glucose, and sucrose, discriminability always declined to chance over a narrow range of test concentrations. At concentrations < or = 100 mM, maltose was indiscriminable from fructose but discriminable at higher concentrations for 4 subjects. By analogy with the monochromacy of night vision, whereby any two lights are indiscriminable when their relative intensities are suitably adjusted, we call the gustatory indiscriminability of these sugars monogeusia. The simplest account of monogeusia is that all information about the indiscriminable sugars is represented by a single neural signal that varies only in magnitude. The discriminability of maltose from the other sugars at higher concentrations is consistent with the hypothesis that maltose also activates a second gustatory code.

Taste interactions between salts (NaCl, LiCl, KCl, L-arginine:L-aspartic acid, Na-acetate and Na-gluconate) and bitter-tasting compounds (urea, quinine HCl, magnesium sulphate, KCl, amiloride HCl and caffeine) were investigated. In each study binary combinations of three or four concentrations of one bitter compound with four concentrations (0, 0.1, 0.3 and 0.5 M) of one salt were rated for bitterness and saltiness using the method of magnitude estimation. In most cases, perceived bitterness was suppressed by salts, although the degree of suppression varied. In general, bitterness suppression was not accompanied by an equivalent reciprocal suppression of saltiness. Only MgSO4 and amiloride had suppressing effects on the saltiness of NaCl at the intermediate concentrations and no bitter compound affected the saltiness at the high concentrations of NaCl. Since salt suppressed the bitterness of urea effectively, a detailed analysis of suppression of the bitterness of urea by different salts was conducted. Those studies indicated that the key component in this effect was the sodium or lithium ion for two reasons: first, all three sodium salts and the lithium salt had a suppressive effect on bitterness, whereas KCl did not; secondly, the effect of a salt on suppression of the bitterness of urea was independent of its perceived saltiness; that is, NaCl, Na-acetate (which is perceived as less salty than NaCl), and Na-gluconate (which is perceived as less salty than Na-acetate) reduced bitterness comparably. These results suggest that there is a major peripheral component to the suppression of the bitterness of urea, and perhaps other bitter tasting compounds, by sodium.

The combined effects of taste and physiological state on lick rate for NaCl were systematically evaluated in two experiments. In experiment 1 the lick rates of six groups of rats (Sprague-Dawley) were recorded during the first 3 min of a NaCl drinking bout, where each group received a different concentration. Half of the rats were depleted by injections of the diuretic-natriuretic furosemide (10 mg ip), whereas the other half were not. The inverted U-shaped concentration-response functions for sodium-replete rats peaked approximately at isotonicity. The replete lick rate function was uniformly elevated for rats examined in the sodium-depleted state. In experiment 2 each rat received access to all six solutions within a 40-min test session. Rats were tested twice, once in positive and once in negative sodium balance. The solutions were repeatedly presented in counterbalanced order in a series of 10-s exposures. The replete and deplete functions of the within-group study closely resembled those of the between-group study. When the deplete rats' function was divided into three segments coinciding with the beginning, middle, and end of the 40-min session, the functions were shifted down vertically but retained their shape. In general, sodium-state level dramatically affected the absolute lick rates but did not appear to shift the location of the concentration-response function along the horizontal (i.e., concentration) axis. The form of the function appears to have been determined by oral factors alone.

Alterations in the motivation to ingest sucrose can be quantified by measuring the number and type of oral motor and somatic responses (i.e., taste reactivity [TR]) that are elicited by sucrose. In 2 experiments, rats had intraorally infused sucrose paired with LiCl injections for several trials, or they were injected with LiCl and had sucrose infused every 5 min during the 30-min postinjection period (data from Spector, Breslin, & Grill, 1988). In both experiments, ingestive TR responses decreased, whereas aversive TR responses increased over trials. Individual response components that comprise the ingestive and aversive categories followed the same trends of increase or decrease but changed at different rates as a function of number of trials or exposures. Overall, the array of response components could be projected onto a single unidimensional scale of palatability to capture the motivational states that ranged from acceptance to rejection.

Oral motor responses, elicited by the infusion of a taste solution into a rat's mouth, can be changed through association with either other tastes or internal states. Such changes have been well established when ingestive responses, elicited by a normally preferred taste, are changed to aversive responses when the taste signals a LiCl injection. However, the converse has yet to be clearly established; that aversive responses, elicited by a normally avoided taste, can be changed to ingestive responses in a nondeprived animal, as a result of conditioning. We demonstrate here that when a normally avoided taste (quinine or HCl) signals a preferred taste (sucrose), the oral motor responses gradually undergo two types of change as a function of trials. The aversive oral motor responses elicited by the avoided taste decrease over trials and the ingestive responses increase. The two measures, ingestive and aversive responding, were obtained by recording the rat's reactions to the stimuli as they were infused directly into the oral cavity. This taste reactivity method both enabled us to use avoided stimuli in a nondeprived animal and to measure the rat's evaluation of the stimuli's aversiveness. Problems with stimulus sampling may be responsible for the dearth of conditioning experiments which utilize avoided tastes in conditioned preference studies.