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Gottfried JA, editor. Neurobiology of Sensation and Reward. Boca Raton (FL): CRC Press/Taylor & Francis; 2011.

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Chapter 12Multiple Reward Layers in Food Reinforcement



Why do animals eat? Virtually any organism must continuously procure from the environment the energy required to maintain vital biochemical processes. For most organisms—insects and mammals alike—the fuel needed to maintain cellular growth and function is obtained from exogenous sources, that is, “food.” Therefore, ingesting fuels that can be either readily oxidized or stored in the body as energy reserves is the ultimate “reward” all living creatures are willing to work for.

In 1947, E. Adolph experimentally manipulated the amount of calories available to rats and noticed that, when next presented with free access to food, these animals adjusted caloric intake by immediately increasing the amount of food ingested (Adolph 1947). Upon considering such evidence, Adolph readily concluded that “rats eat for calories.” These early observations suggested that animals regulate their intake as a response to the body’s metabolic needs. In other words, the postingestive effects produced by metabolically efficient foods exert by themselves reinforcing effects on behavior—a hypothesis that, we shall see, has since then gained strong experimental support.

Adolph (1947) did also notice, however, that the regulation of food intake must be under many influences. Among these—besides caloric content itself—are the multiple sensory properties of foods, such as their taste, odor, texture, and appearance. To this list we should add those initially neutral environmental signals that incrementally acquire predictive functions via associative learning. These diverse sensory aspects of food stimuli can by themselves motivate behavior, by functioning as proximal or distal indices of nutritive value. The many detectable sensory features associated with the actual metabolic value of a food form “layers” of cues that gain motivational value by themselves, and are critical for the ability of an organism to locate fuels in a fast, efficient manner.

In other words, the behavioral processes controlling food intake must be understood as resulting from a summation of relatively independent “layers of reward” that act to sustain positive energy balance. For example, sugars can be considered as prototypical “bilayered” rewards: energy-carrying molecules that also are highly palatable* (i.e., capable of inducing intake via stimulation of sweet receptors). To these layers are associated reward signals that are either “proximal” to the consummatory act of eating itself (such as the taste of foods) or more “distal” (see Figure 12.1 for a scheme), such as anticipatory visual and olfactory cues predicting food delivery (Gottfried, O’Doherty, and Dolan 2003), or the rewarding postconsumptive effects produced by nutrients. Potentially, “preingestive” distal cues (i.e., those occurring prior to the act of ingestion) have different physiological functions from those associated with postingestive distal cues, particularly with regard to the encoding of predictive value. The implication is that different brain regions are involved in the representation of pre- and postingestive distal cues.

FIGURE 12.1. Proximal and distal cues associated with food reinforcement.


Proximal and distal cues associated with food reinforcement. Proximal cues can be defined as those sensory cues that are associated with the consummatory act of eating itself; it might include inputs such as the taste and the texture of a food, or its (more...)

The question now arises, which of these more proximal and distal cues constitute the critical rewarding event in food preferences. It has been long thought that the main drivers of food intake are those sensations associated with the food’s taste or palatability. In fact, the perceptual quality of sweet taste is so compelling and familiar to us that we might well be led to assume that the sensation of “sweetness” constitutes the essence of what we call “sugar reward” (idea that sweetness does not necessarily a reward make, see Chapter 6). Part of this impression certainly arises from our innate and almost universal attraction to non-caloric “artificial” sweeteners: their potent palatability seemingly indicates that calorie-independent sweetness is the central factor or “reward layer” governing our strong preferences for carbohydrate-rich compounds.

However, the formation of long-term food preferences is a complex process and it shouldn’t be automatically assumed that animals will form preferences for palatable, sensory cues when those come unaccompanied by postingestive effects. In fact, as we will argue in this chapter, the critical reward event occurring during food intake seems to be the triggering of postingestive processes that follow food intake. More precisely, current evidence would suggest that postingestive effects are both necessary and sufficient for the formation of preferences towards calorie-rich nutrients. On the other hand, gustatory cues do not seem to have the ability to sustain long-term preferences if unaccompanied by postingestive factors. In other words, the experimental data available so far indicate that a hierarchy exists in which distal, delayed postingestive effects function as the principal factor regulating nutrient choice, at least over extended periods of time.

How can the brain regulate food intake, given that preferences seem to be under the simultaneous control of different distal and proximal events? One possibility is that a brain circuit exists that has the ability to respond to all behaviorally relevant distal and proximal cues. We will argue that the mammalian midbrain dopamine system is one such candidate circuit,* given its prominent role in food reward processing and its ability to detect and respond not only to proximal cues such as palatable tastes but also to distal cues that acquire predictive power through learning. In addition, and consistent with the preponderant role played by postingestive factors in food intake, we will also review recent evidence showing that the detection of nutrient processing from its absorption in the gut is sufficient to activate the mesolimbic dopamine system in the absence of gustatory or flavor stimulation. We will explore some of the implications of these findings and the many related questions that remain unanswered.


12.2.1. The Labeled-Line Model of Gustatory Coding

Direct stimulation of some taste receptor cells can, by itself, exert reinforcing control on food intake. The psychophysical and neural bases of gustation have been reviewed elsewhere in this volume (see Chapter 6). The purpose of this section is to provide the reader with the basic terminology employed in the following sections.

An ongoing debate as to how taste qualities are coded has been the focus of attention of taste researchers for many years now. In one view, named the “across-fiber pattern” model, perceived taste qualities correspond to patterns of activity across afferent nerve populations (Erickson 2001). An alternative, opposing view proposes instead a “labeled-line” model, in which different taste qualities are encoded by separate peripheral circuits defined by subsets of taste cells expressing specific chemosensors in connection with the afferent neurons upon which they synapse. If, on one hand, the existence of broadly tuned gustatory neurons has been argued to give support to the across-fiber model (Boudreau et al. 1985; Frank, Bieber, and Smith 1988; Caicedo, Kim, and Roper 2002), evidence is mounting in favor of the existence of dedicated, labeled lines transducing taste signals to the central nervous system (for a different perspective see Lemon and Katz 2007).

The first line of evidence arises from the receptor distribution patterns on the tongue. Three types of taste sensations are known to be mediated by G-protein-coupled receptors, in their turn divided into two broad groups, namely, T1Rs and T2Rs, whose function is at least in some cells supported by the alpha component of the taste-specific G-protein gustducin (α-gustucin, McLaughlin, McKinnon, and Margolskee 1992). On one hand, the T1Rs mediate behavioral attraction to nutritive tastants via the sweet-detecting heterodimer T1R2/T1R3 (and possibly the homodimer T1R3/ T1R3) and the L-amino acid-detecting T1R1/T1R3 heterodimers (Zhao et al. 2003). On the other hand, repulsive bitter taste sensations are mediated by the T2R family of receptors (Chrandrashekar et al. 2000). Importantly, it has been established that none of those receptors co-express in taste cells (Chrandrashekar et al. 2000). Therefore, the anatomical substrate is in place to support network-dedicated, labeled lines of taste transduction for sweet, L-amino acids, and bitter (Damak, Mosinger, and Margolskee 2008).

Another line of evidence supporting the existence of these dedicated lines relates to the concept of restricting the expression of some essential components of the intracellular taste signaling cascade to a limited, receptor-specific group of cells. For example, expressing the phospholipase Cβ2 only in taste cells that express the bitter receptor T2R5 (which selectively binds to cyclohexamide, a toxic bitter compound) results in normal detection of bitter but not sweet or L-amino acid tastes (Zhang et al. 2003). In addition, restricting the transgenic expression of a modified opioid receptor to cells that contain T1R2 receptors (i.e., in cells specifically tuned to sweet tastes) results in preferences for a tasteless synthetic opiate similar to those found for sucrose (Zhao et al. 2003). Conversely, when the same opiate receptor was selectively expressed in “bitter” cells (i.e., T2R-expressing taste cells), the animals displayed a rejection to the synthetic opiate in a manner that emulates rejection to bitter compounds. Finally, it is of note that in mice produced to express bitter T2R receptors in “sweet” cells (i.e., T1R2-expressing cells), a sugar-like attraction for bitter tastants is observed (Mueller et al. 2005). Such genetic manipulations therefore strongly suggest that behavioral responses produced by tastants are mediated by a highly specific subset of taste cells whose activation is necessary and sufficient to elicit stereotyped behavioral responses. In particular, these findings imply that different stereotyped behaviors are mediated by non-overlapping groups of taste cells, a fact that considerably weakens the possibility that taste transduction depends on distributed patterns of activity in the periphery.*

12.2.2. The Dopamine Mesolimbic Pathway and Palatability

How does the brain, more specifically its reward-processing centers, respond to the stimulation of T1R taste cells? Judging from the stereotypical, appetitive responses elicited by mere stimulation of “sweet” cells even when expressing exogenous receptors, one would expect that brain circuits involved in processing reward information must be sensitive to sensory stimulation independently of the physiological consequences of ingesting the ligands. The role of brain dopamine systems in mediating food reward, and in encoding stimulus palatability, has been well established. Dopamine antagonists attenuate the hedonic value of sweet-tasting nutrients, in that animals pretreated with either D1- or D2-type dopamine receptor antagonists behave toward high concentrations of sucrose solutions as if they were weaker than usual (Xenakis and Sclafani 1981; Geary and Smith 1985; Bailey, Hsiao, and King 1986; Wise 2006). Conversely, tasting palatable foods elevates dopamine levels in the nucleus accumbens (NAcc) of the ventral striatum (Hernandez and Hoebel 1988), a brain region largely implicated in food reinforcement (Kelley, Schiltz, and Landry 2005). In humans, striatal dopamine release directly correlates with the perceived hedonic value of food stimuli (Small, Jones-Gotman, and Dagher 2003). But is dopamine release induced by sweet palatability per se independent of carbohydrate metabolism? In fact, taste-elicited stimulation of the central dopamine systems seems to take place even in the absence of intestinal nutrient absorption. In “sham-feeding” studies where a catheter is implanted in the stomach to prevent nutrients from reaching the intestinal tract, accumbens dopamine levels increase in proportion to the concentration of the sucrose solution used to stimulate the intraoral cavity (Hajnal, Smith, and Norgren 2004).

It is therefore plausible to assume that the events leading to the stimulation of brain reward circuits via dopamine release are initiated within the oral cavity, upon the activation of taste receptors. This implies that the dopamine release effect in accumbens related to sweet taste stimulation must depend on the integrity of central taste relays conveying gustatory information to downstream brain circuits. In fact, the parabrachial nucleus seems to be required for accumbens dopamine levels to increase upon gustatory stimulation. In rodents, axonal fibers originating in the gustatory aspect of the nucleus of the solitary tract ascend ipsilaterally to the parabrachial nucleus, establishing this pontine structure surrounding the conjunctivum brachium as the second-order gustatory relay (see Chapter 6 in this volume; and Norgren and Leonard 1971, 1973; Norgren and Pfaffmann 1975). The parabrachial nucleus is typically divided into two main portions, medial and lateral, relative to the conjunctivum brachium (Reilly 1999). Concerning this division, both anatomical and electrophysiological evidence suggest that parabrachial nucleus taste neurons are located primarily in medial subnuclei (Perrotto and Scott 1976; Fulwiler and Saper 1984; Ogawa, Hayama, and Ito 1987).

Dopamine release upon palatable taste stimulation seems to be mediated by projections to limbic circuits originating in the parabrachial nucleus in a way that is independent of thalamic relays.* In fact, whereas one group of projections from PBN reach the insular cortex via the taste thalamic relay (Norgren and Wolf 1975), a second, separate pathway reaches the amygdala, lateral hypothalamus and the bed nucleus of the stria terminalis (Norgren 1976; Li, Cho, and Smith 2005). Thus, it has been shown that lesions to the PBN limbic, but not to the PBN thalamocortical, pathway blunt the dopaminergic response during intake of palatable tastants (Norgren and Hajnal 2005; Norgren, Hajnal, and Mungarndee 2006). Such effects were further confirmed by experiments using c-fos measurements (Mungarndee et al. 2004).

12.2.3. Palatability and the Formation of Long-Term Food Preferences

Consistent with what is now known about the labeled-line molecular logic of taste transduction, it would be straightforward to assume that the sensation of sweetness exerts a potent attractive effect on brain reward systems and, therefore, on behavior. Indeed, both deprived and non-deprived animals will not only avidly consume sweet solutions, but also run through intricate mazes or incessantly press levers to obtain sweet rewards (Kare 1971). In general, the expression of those motivated behaviors will increase with the concentration of the sweet tastant in the solution.

The hedonic sensation of sweetness is innate in humans. This is demonstrated by the reactions observed in children upon their first exposure to sugary solutions: the newborns will immediately suck the solutions and produce characteristic facial expressions (Ganchrow, Steiner, and Daher 1983). In rats, pups as young as six days old are strongly attracted to sweetness, given their robust intake responses to sweet compounds such as sucrose, lactose, and saccharin (Hall and Bryan 1981). It is also well established that other species show similar attractions to sweet compounds at early ages (Houpt, Houpt, and Pond 1977).

The strength of the reinforcing properties of sweet compounds is illustrated by their ability to form associations with and elicit increases in intake of arbitrary flavors, an effect denominated “flavor-taste conditioning.” In this case, a distinct and moderately pleasant flavor functions as a conditioned stimulus at the same time as an innately pleasant stimulus such as sweet taste functions as the unconditioned stimulus. In this design, a flavor cue may gain motivational value through flavor-taste conditioning if its presentation is paired with another taste or flavor that is hedonically positive to the animal. For example, combining a given arbitrary flavor with a sweet tastant in a solution will increase intake levels of this flavor when experienced alone, presumably due to the learned previous associations between the flavor and the palatable sweet taste (for a review Myers and Sclafani 2006). In other words, the consummatory responses to an arbitrary flavor can be made to increase via conditioning when associated with a palatable flavor, such as those associated sweet compounds.

However, are the reinforcing properties of sweet tastes sufficiently strong to influence intake in the long term? Although the sensory hedonic properties linked to taste and flavor are associated with high levels of intake in the short term (i.e., from minutes to a few hours), there is currently no definite evidence that such sensory properties regulate or even enhance longer-term increases in caloric intake.

In fact, in a series of experiments performed during the 1980s, Naim, Kare and colleagues investigated the role of sensory input in long-term experiments in rats where the nutritional composition of the food was controlled (Naim et al. 1985, 1986; Naim, Brand, and Kare 1987). The first, overall goal of these experiments was to verify whether supplementing the diets with highly preferred flavors and textures was sufficient to enhance long-term caloric intake of foods low in sugar or fat content. The second aim was to verify whether an effect would be observed in flavor-supplemented diets containing higher levels of sugar or fat. This last experimental manipulation was intended to mimic the composition of high-caloric diets whose consumption is associated with the development of obesity.

The results of these experiments are, to say the least, intriguing. Overall, they strongly suggest that palatable flavors and textures incorporated into the diets did not induce overconsumption of calories at any time up to 23 days (Naim and Kare 1991). Most interestingly, the added flavors increased intake during the first five days, but not thereafter. Such results were not replicated for the case of high-fat diets (Naim et al. 1985). Taken together, these results suggest that adding flavors and textures to non-caloric diets did not affect intake in rats except for a short and transient effect on intake over the first five days of the experiment.

The associative strength of palatable non-caloric compounds can be directly contrasted to those of caloric but less palatable ones. Consistent with the above, Fedorchak and Bolles (1987) have shown that pairing flavor-conditioned stimuli with caloric compounds produces a stronger effect on flavor preferences compared to palatable ones. Exposures to fruit flavors were paired with either caloric ethanol (in doses that do not seem to produce major aversive/irritant effects), non-caloric sweet saccharin (sweet but non-caloric), or water. During the post-training two-bottle choice tests, it was concluded that flavors associated with ethanol were preferred over saccharin-paired and water-paired flavors by sated rats, and that food deprivation during the choice test enhanced this preference. In addition, flavors associated with 8% sucrose (caloric and sweet) were preferred over water-paired flavors during ad libitum testing, an effect that was enhanced by hunger. Overall, calorie-mediated preferences were stronger than taste-mediated preferences. Fedorchak and Bolles (1987) then concluded that hunger enhances the expression of calorie- but not taste-mediated conditioned flavor preferences.

Similar conclusions could be inferred concerning the more specific role of sweet taste in carbohydrate intake. One would say, as noted in the Introduction, that sweet taste would underlie the excessive intake of calories associated with sugars. However, adding sucrose to solid diets results in no gain, or even loss, of body weight (Cohen and Teitelbaum 1964). On the other hand, although sucrose solutions do enhance caloric intake and may lead to obesity, the same effect is observed with non-sweet carbohydrate solutions such as Polycose (a polysaccharide) solutions (Sclafani and Xenakis 1984). Even more revealing is the fact that rats, when offered solutions containing an unpalatable mixture of Polycose and SOA (a bitter tastant), will consume amounts of that solution comparable to that of an alternative solution containing a saccharin-Polycose mixture (Sclafani and Vigorito 1987). Therefore evidence is lacking for a preponderant role of sweet taste in excessive carbohydrate intake.

A more recent demonstration that palatable tastes, when unaccompanied by metabolic effects, lack the ability of inducing longer-term preferences was given in a study using mice, where animals were required to express their preferences for sipper positions previously associated with the delivery of either caloric sucrose or sucralose, a non-caloric but strongly sweet sucrose-derived compound (de Araujo et al. 2008). In this behavioral model, animals are allowed to form an association between a particular sipper in a behavioral test chamber and the postingestive effects produced by drinking from that sipper. This is accomplished in sweet-naïve animals by first determining the initial side-preferences using a series of preliminary two-bottle tests where both sippers contained water. Hungry and thirsty mice are then exposed to a conditioning protocol where alternating access to either water or caloric sucrose was given for six consecutive days. Conditioning sessions consisted of daily 30 minutes free access to either water (assigned to the same side of initial bias) or caloric sucrose (assigned to the opposite side) while access to the other sipper was blocked (see Figure 12.2a–c for a scheme of the behavioral task). As expected, wild-type, taste-enabled mice consumed significantly more sucrose than water during the conditioning, one-bottle sessions (Figure 12.2d). The conditioning sessions were then followed by two-bottle, water-water tests identical to those run to determine initial side biases. During test sessions, the mice reversed their initial side-preference biases by drinking significantly more water from the sipper that during conditioning sessions had been associated with caloric sucrose, with preference ratios of up to 80% (Figure 12.2f).

FIGURE 12.2. A conditioning protocol to study the reward value of postingestive effects independently of taste signaling.


A conditioning protocol to study the reward value of postingestive effects independently of taste signaling. Behavioral protocols can be used for studying the formation of food preferences based on taste-independent, postingestive effects. Hungry and (more...)

When the same conditioning experiments were performed on an additional group of naïve animals, but this time using a non-caloric sucralose solution, a similar result was observed during conditioning sessions in that the animals consumed significantly greater amounts of sucralose compared to water (in fact, intake levels were even higher than those observed for sucrose). However, and rather importantly, during the postconditioning two-bottle test sessions these animals failed to display preference for the sippers associated with the delivery of sucralose, with preference ratios around 50%. Such inability of palatable non-caloric, unlike caloric, compounds to induce the formation of side preferences in behavioral tests indicates that palatability per se is not sufficient to produce the behavioral modifications necessary for animals to develop long-term consummatory behaviors.

Taken together, the studies described above strongly suggest that orosensory factors play a relatively minor role in the long-term increase in energy intake and associated adiposity in rats and mice. Rather, it seems that postingestional factors, related to the caloric content and/or metabolic effects of nutrients, are a major regulator of food intake over extended periods of time. The behavioral and physiological aspects of postingestive factors are explored in the following sections.


12.3.1. Postingestive Regulation of Food Intake

Postingestive factors refer to physiological events subsequent to the consummatory act of eating. Postingestive factors include both pre- and postabsorptive events. The former include events such as gastric distention and stimulation of nerve terminal sensors throughout the gut epithelium, whereas the latter relate to physiological responses that follow nutrient absorption by the gut such as fuel oxidation or deposition, along with increases in plasma hormonal levels. The question of whether the critical reinforcing postingestive event is pre- or postabsorptive remains pretty much open for debate (although see the considerations in this chapter). In any event, the importance of postingestive factors as main regulators of food intake is now generally accepted, and new methodologies allowing for the experimental analysis of postingestive effects are being actively pursued.

Inquiries on the possibility that postingestive effects could act as regulatory factors in the absence of orosensation were taken on as early as the 1950s. In an intriguing study, Miller and Kessen (1952) infused either milk or saline intragastrically in rats depending on which arm of a T-maze they entered. The found that under a rather extended period of time (approximately 40 days) the rats developed the habit of entering the maze associated with milk infusion. Although the authors also noted that rats that were allowed to drink the solutions were able to learn the maze task much faster, this experiment constituted an early demonstration that postingestive effects are sufficient to sustain learned preferences for nutrients, although learning can be greatly facilitated by orosensory inputs.

Another series of pioneering experiments was performed by Epstein, Teitelbaum and colleagues (Epstein and Teitelbaum 1962; Epstein 1967). The researchers prevented rats from eating foods while allowing them to obtain intragastric infusions of nutrients by pressing a lever. They showed that the number of lever presses produced by the rats were essentially a function of the amount of nutrient infused via the gastric cannulae, with lower amounts of nutrients producing higher number of responses (presumably this corresponds to a compensatory response pattern). More precisely, in the cases where infused amounts were minimal, rats achieved stable levels of nutrient intake by increasing lever press frequency in such a way that body weight was eventually restored to normal levels. Similar experiments by Miller and Kessen (1952) further corroborated the principle that postingestive factors are sufficient to control caloric intake. It is also interesting to note that humans will also work to infuse diets intragastrically in order to maintain their necessary levels of nutrition (Jordan 1969).

Although it had become clear by the late 1960s that postingestive effects act as main regulators of food intake, some researchers became interested in the more specific question of whether these effects, specifically in the form of intragastric infusions, can influence or even increase preferences for certain foods. One elegant way to answer such a question would require experimental paradigms where the orosensory properties of food are paired with intragastric infusions. Holman (1968) introduced such a protocol, in which exposure of rats to a flavored drink for five minutes was immediately followed by an intragastric infusion of either a nutrient or water. The training sessions were six in total, with three of them allowing the animals to form an association between one flavor and the postingestive effects produced by infused nutrient, and the other three between another flavor and infused water. During subsequent two-bottle tests, Holman (1968) observed that the vast majority of rats preferred the flavor that had previously been paired with nutrient infusion. This seems to have been the first demonstration of what had come to be known as “flavor-nutrient conditioning,” that is, that preferences for distinct flavor can develop as a function of the postingestive effects produced by the flavored food.

How likely is it, however, that paradigms where flavored drinks are paired with intragastric infusions of nutrients reproduce the physiological processes by which caloric food acquires motivational value through experience? Booth seems to have been the first one to attempt to produce conditioned flavor preferences using nutritive flavored foods (Booth 1972). In these experiments rats were fed different flavored foods that however varied with respect to their starch content. When the rats were given a choice between the different foods whose particular flavors had been previously associated with different starch contents, Booth (1972) observed that the animals preferred the flavored food associated with the highest caloric content (during the test, flavored foods were all presented at equally moderate caloric levels). Further variations of this experimental design include the interesting case where the differently flavored foods each associated with a specific caloric value are presented simultaneously to animals (Bolles, Hayward, and Crandall 1981), demonstrating that several days of exposure will eventually lead to a long-lasting preference for the flavored foods paired with higher caloric content.

It could therefore be concluded that pairing of distinct flavored drinks with intragastric infusion does realistically model the physiological processes that enhance flavor preferences following long-term exposure. This method has been successfully adopted by other researchers (Mather, Nicolaidis, and Booth 1978; Tordoff and Friedman 1988; Tordoff 1991; Sclafani 2001). One advantage of this method is that it can be employed virtually ad infinitum if one considers the number of all possible combinations involving distinct flavors, nutrients, and their concentrations. In fact, Sclafani and colleagues have been employing the flavor-nutrient conditioning method repeatedly, providing useful information concerning the relative reinforcing strength of different nutrients (reviewed in Sclafani 2001).

Despite its elegance and efficiency, the flavor-nutrient method based on intragastric infusions does not shed light on a crucial issue, namely whether ingestive behaviors can be actively sustained in the absence of oropharyngeal flavor sensation. In fact, the flavor-nutrient conditioning protocol necessarily pairs intragastric infusions of nutrients with flavor stimulation, leaving open the question of whether sensory stimulation by distinct flavors is required to sustain normal ingestive behaviors. Obviously, it must be noted that in the atypical case that flavor cues are absent, other sensory features associated with the food object would have to be present to allow for associations with ensuing postingestive effects to be formed; such non-orosensory cues include, for example, the spatial location of the food. In general, whatever the nature of the sensory cues involved, these internal representations or memories can then be rapidly accessed and retrieved through incentive learning processes when the animal next encounters the food object (as discussed in Chapter 13).

The question above can be more clearly addressed if the ability to detect the sensory properties of distinct flavors is prevented from occurring during the experiments. One way to achieve this refers to using genetically engineered animals lacking taste sensation. As explained above, a conditioning protocol can be used where wild-type mice will develop a preference for drinking, during postconditioning two-bottle water vs. water tests, from the sipper location previously associated with nutritive sucrose but not with the location associated with the non-nutritive sweetener sucralose (de Araujo et al. 2008). The same study also employed mice lacking a functional transient receptor potential channel M5 (Zhang et al. 2003). The TRPM5 ion channel is expressed in taste receptor cells (Perez et al. 2002) and is required for sweet, bitter, and amino acid taste signaling (Zhang et al. 2003). It was hypothesized in this study that sweet-blind trpm5 knockout mice would develop a preference for spouts associated with the presentation of sucrose solutions when allowed to detect the solutions’ rewarding postingestive effects.

Once the insensitivity of KO mice to the orosensory reward value of sucrose was established, de Araujo et al. (2008) tested whether a preference for sippers associated with caloric sucrose solutions could develop in water- and food-deprived trpm5 knockout mice when they are allowed to form an association between a particular sipper in the test chamber and the postingestive effects produced by drinking from that sipper. As explained above, this was accomplished in sweet taste-naïve animals by first determining the initial side-preferences using a series of preliminary two-bottle tests where both sippers contained water and by exposing animals to conditioning sessions consisting of daily 30 minutes free access to either water (assigned to the same side of initial bias) or sucrose (assigned to the opposite side) while access to the other sipper was blocked (Figure 12.2a–c).

Analysis of the behavioral data across both wild-type and knockout mice revealed no significant genotype x stimulus interaction since during conditioning sessions both wild-type and knockout animals consumed significantly more sucrose than water (Figure 12.2d, e). In addition, during the postconditioning two-bottle tests, it was observed that both wild-type and knockout animals reversed their initial side-preference biases by drinking significantly more water from the sipper that during conditioning sessions had been associated with nutritive sucrose (Figure 12.2f). Now, when the same experiments were instead run using sucralose (palatable but lacking nutritive benefits), unlike for the sucrose case, a Significant genotype × stimulus interaction was found because only the wild-type animals consumed significantly more sucralose than water during the conditioning sessions. Furthermore, during the two-bottle test sessions, conducted after conditioning to sucralose, knockout mice, like their wild-type counterparts, showed no preferences for sippers associated with the delivery of sucralose. Overall, these results provide evidence in favor of the hypothesis that postingestive effects can exert positive controls on ingestive (licking/swallowing) behaviors even in the absence of taste signaling or detection of distinct flavors.

12.3.2. The Postingestive Reward Signal

While there is little disagreement that postingestive factors produced by nutrients regulate food intake, much more controversial is the nature of the signal that acts on the brain as a postingestive reinforcer. Broadly speaking, the candidate signals can be classified into two groups, related to pre- and postabsorptive events. The former group concerns those sensing mechanisms that occur before nutrient absorption but simultaneous with the arrival of nutrients to the gut. The latter group refers to those events that occur following absorption, and non-exclusively includes a variety of signals such as fuel oxidation metabolites and changes in plasma hormonal levels. In this section, we review some of the mechanisms proposed so far to function as the postingestive reward signal. Preabsorptive Mechanisms Orosensory signals

As argued above, orosensory signals including taste or other flavor additives constitute weak reinforcers when employed as unconditioned stimuli during flavor conditioning paradigms. Overall, calorie-mediated preferences are stronger than taste-mediated preferences (Fedorchak and Bolles 1987; Naim and Kare 1991). In addition, mice lacking the cellular machinery required for taste transduction do develop robust preferences for sources of sucrose delivery (de Araujo et al. 2008). These facts strongly suggest that delayed oropharyngeal sensations do not account for the development of food preferences based on postingestive effects. Gastric Signals

We could in principle start by ruling out as reward signal candidates the visceromechanical signals from the gut. These include pressure-related signals reaching the brain upon nutrient arrival in the stomach. In fact, because only nutrients, but not water, saline, or artificial sweeteners can produce postingestive reinforcement in flavor-nutrient conditioning paradigms, simple mechanical pressure on gut nerve terminals could not be the primary source of a central reinforcement signal.

It could be claimed, however, that different compounds might induce different transit/gastric emptying time-courses (Friedman, Ramirez, and Tordoff 1996), and that these differential patterns in gastric activity could act centrally to communicate information to the brain regarding the presence and processing of nutrients in the gut. This is consistent with the concept that liquid nutrient gastric emptying represents an interaction between gastric volume and nutrient-induced duodenal feedback (Moran et al. 1999). However, this hypothesis becomes less plausible if one considers the early studies performed by Tsang (1938) on gastrectomized hungry rats. Tsang removed over 90% of the stomach from rats before their behaviors in food-baited mazes and cages were studied. Interestingly, after 24 hours of fasting, gastrectomized rats were nearly as well motivated as normals in the first trial of the maze. These studies showed in general that gastrectomy will cause an increase in overall motivation, certainly because the animals sought to compensate for the decreased caloric intake resulting from having a drastically reduced stomach. Although Tsang (1938) noted that an empty stomach is likely to be a necessary condition for motivation for food, contractions of the stomach per se cannot underlie the source of the motivation.

Consistent with the above, it was later found that gastric vagotomy does not interfere with habitual feeding patterns in rats (Snowdon and Epstein 1970), and more recently it was shown that abdominal vagotomy does not interfere with flavor preferences conditioned by Polycose (Sclafani and Lucas 1996). Taken together, all of these lesion-based studies weaken the idea that gastric signals function as central reinforcement signals, suggesting that other mechanisms downstream to gastric emptying are involved. Preabsorptive Intestinal Signals and Gut Taste Receptors

What evidence is there in favor of a preabsorptive postingestive reinforcement signal originating from the gut epithelium, more precisely in the intestinal tract? One simple way to test whether such mechanisms exist in the first place is to prevent nutrient absorption during flavor-nutrient conditioning tests and observe the ensuing behavioral responses. To test this hypothesis Elizalde and Sclafani (1988, 1990) exposed rats to two flavored drinks, only one of which contained the non-sweet poly-saccharide Polycose. However, for one group of rats, the flavored Polycose drink also contained acarbose, an inhibitor of starch hydrolysis, effectively preventing Polycose-derived glucose from being absorbed in the duodenum. While the animals that were exposed to the Polycose-only drink developed robust preferences for the associated flavor, those exposed to the Polycose+acarbose drink did not. This finding challenges the idea that preabsorptive mechanisms constitute a major reinforcement signal in postingestive reward.

The above would indicate additionally that a fundamental role might be played by intestinal glucose transporters in postingestive reinforcement, at least for the case of carbohydrates. The intestine has the ability to modulate its glucose-absorptive capacity by regulating the expression levels of the intestinal sodium/glucose co-transporter 1 (“SGLT1,” Dyer et al. 2003). Unfortunately, the precise contribution of SGLT1 (or related proteins such as SGLT3) expression in the gut to carbohydrate postingestive reinforcement has not yet been investigated. However, recent developments have demonstrated that gastrointestinal epithelial cells express many of the known (taste) receptors and downstream factors located in taste cells of lingual epithelium. This finding is important for the understanding of postingestive reinforcement because it potentially provides a molecular basis for gut chemosensation, whose signals could possibly be conveyed to the brain, informing of the presence and composition of nutrients in the lumen.

With regard to the intestinal epithelium, the alpha component of the taste-specific G-protein gustducin (α-gustducin, McLaughlin, Mckinnon, and Margolskee 1992) was shown to be present in brush cells of the rat proximal intestine (Hofer, Puschel, and Drenckhahn 1996), as well as in mouse intestinal endocrine cells and enteroendocrine cell lines (Wu et al. 2002). More recently it was shown that T1R receptors are also present in the rodent gut epithelium as well as in enteroendocrine cell lines (Dyer et al. 2005). Importantly, α-gustducin, T1R2, and T1R3, as well as other taste signaling proteins including the taste ion channel TRPM5, are co-expressed in some mouse and human enteroendocrine cells (Bezençon, le Coutre, and Damak 2007; Margolskee et al. 2007). These co-expression data are extremely relevant since the concomitant presence of at least a subset of these proteins in lingual taste cells is required for normal taste transduction. In general, these results strongly suggest that the intestinal epithelium can “taste” dietary composition and possibly provide a signal to the brain on postingestive events taking place after eating.

What evidence is currently available regarding the physiological functions of these gut-expressed taste signals? Although research is still in progress, convincing evidence exists that both α-gustducin and T1R receptors regulate the expression levels of SGLT1 in the intestine. More precisely, Margolskee and colleagues (2007) have used mouse knockouts lacking α-gustducin or T1R3 to show that the absence of either of these signals blocked the ability of dietary sugars, as well as of artificial sweeteners, to up-regulate the expression of SGLT1. Interestingly, SGLT1 expression levels in both types of knockout mice were similar to those of wild-type mice fed a low-carbohydrate diet. This indicates the existence, in addition to basal SGLT1 expression levels, of a signaling cascade pathway that is initiated by T1R3/α-gustducin activity to increase expression levels of SGLT1 in response to luminal sugars (Jang et al. 2007; Margolskee et al. 2007; Egan and Margolskee 2008).

However, do these data provide evidence that gut-expressed taste-related proteins play a role in postingestive reinforcement? The behavioral data describing postingestive regulation of sugar intake in TRPM5 knockout mice (de Araujo et al. 2008) contributes to the ongoing debate on whether nutrient-sensing by the gastrointestinal system makes use of taste-like transduction pathways to detect luminal contents and regulate nutrient absorption. Indeed, the fact that TRPM5 knockout animals developed a preference for the sipper locations associated with sucrose availability, whereas wild-type animals did not condition to sipper locations associated with sucralose (a non-caloric substance that activates the same taste transduction pathways as sucrose), indicates that the presence of the taste TRP channel M5 in the gastrointestinal tract (Bezençon, le Coutre, and Damak 2007) is neither necessary nor sufficient for sweet nutrients to act centrally as reinforcers. This behavioral observation was further strengthened by the fact that during sucrose intake knockout animals displayed changes in blood glucose levels comparable to those observed in wild-types. Furthermore, a similar conclusion was recently reached based on the long-term consummatory patterns produced by T1R3 knockout mice (Zukerman et al. 2008). It was observed in this study that T1R3 knockout mice did develop a preference for sucrose solutions over a few days of exposure. The authors attributed the experience-induced sucrose preference to a post-oral conditioned preference for non-sweet orosensory features of the sugar solutions (odor, texture, etc.). Independently of which cues were used by these animals, the results clearly indicate that T1R3, and likewise TRPM5, expression in the gut epithelium is not required for mice to detect the postingestive effects of sucrose.

Taken together, the results above demonstrate that taste proteins essential for sweet taste transduction in lingual epithelium are not required for sucrose to act centrally as a postingestive reinforcer, despite the putative role of these proteins in modulating SGLT1 expression in the gut epithelium. Judging from the available data, it seems more plausible to think that gut taste proteins are more specifically related to the controlled release of endocrine factors by the gut. Postabsorptive Mechanisms

A number of postabsorptive mechanisms have been suggested to act as the reward signal controlling conditioned responses to food via postingestive reinforcement. We review some of the current evidence in their favor below. Hepatic Mechanisms

The first investigator to propose a “hepatostatic” theory of food control was M. Russek (1970, 1981). Russek’s theory seems to have evolved from his early observations that dogs displayed a reduced appetite for food when they were given hepatic-portal infusions of glucose. Even more interesting was the finding that conditioning the hepatic glucose infusions to the presentation of a light caused animals to reduce food intake while being exposed to the light even in the absence of infusions (Russek 1970). Although Russek considered these postingestive and associative effects to be of a preabsorptive nature, i.e., mediated by sensory activation of autonomic fibers, it established the then original concept that the central organ for glucose homeostasis might play a central role in feeding.

The study of the role of the liver in conditioned food intake was done in greater depth by M. Friedman, M. Tordoff and colleagues (Tordoff and Friedman 1988, 1994; Tordoff, Rawson, and Friedman 1991; Friedman et al. 1999; Friedman 2007). In one important experiment using rats, a flavor-nutrient design was employed where the unconditioned stimulus consisted of hepatic-portal infusions of either glucose or saline (Tordoff and Friedman 1986). During test sessions, the rats preferred the flavor that had been associated with hepatic (but not jugular) glucose infusions, demonstrating that glucose detection in the portal-hepatic system, bypassing the gastrointestinal tract, is sufficient to provide a brain with a postingestive reinforcement signal.

Different carbohydrates will differentially tax the liver with singular metabolic demands. Therefore, another way to assess the role of the liver in postingestive reinforcement relates to comparing the differential effects produced by different carbohydrates when employed as unconditioned stimuli in flavored food-nutrient conditioning paradigms. In fact, whereas glucose is absorbed and utilized as fuel by muscle, brain, and other tissues besides the liver, fructose greatly differs from glucose in the sense that its greater utilization occurs in the liver, with fructose being unable to cross the blood-brain barrier (Tordoff 1991). Consistent with a hepatostatic theory of conditioned food preferences, rats developed a strong preference for flavors paired with fructose drinks over those paired with glucose drinks. These experiments seem to indicate that the liver is a crucial site for the generation of reinforcement signals in conditioned food intake.

Intriguingly, later experiments comparing the effects of fructose and glucose in flavored drink-nutrient conditioning paradigms suggested that intragastric fructose infusions provide a weaker postingestive signal compared to glucose infusions (Sclafani, Fanizza, and Azzara 1999). The reason for such a discrepancy is presently not clear and might signify that liver-derived reinforcement signal is superseded by other signals generated during intragastric infusions of sugars. In any case this latter point, if anything, stresses the need for further research on the pathways conveying information of hepatic processes to the brain. Metabolic Signals

Friedman has proposed that food intake patterns are ultimately controlled by signals generated during the oxidation of metabolic fuels (for reviews see e.g., Friedman 1989, 1991). This hypothesis is directly related to the assumption discussed above that the liver is a critical site for the generation of reinforcing signals given the prominent role of this organ in fuel metabolism. From a biological point of view at least, this is probably the most sensible hypothesis one could come up with, since any consummatory behaviors that do not eventually result in fuel utilization should ultimately have no reinforcement value.

This concept is rooted in the experimental observation that inhibition of both glucose utilization and fatty acid oxidation interfere with food intake (Friedman and Ramirez 1985; Friedman et al. 1999). For example, systemic administration of 2-deoxy-D-glucose (2-DG) elicits feeding in rats (Friedman and Tordoff 1986), presumably by inhibiting glycolysis in peripheral tissues and brain and depriving animals of usable energy. In fact, 2-DG is a glucose analogue that competes with glucose for transport through membrane channels and for phosphorylation by hexokinase (Sokoloff 1989), while inhibiting glycolysis at the phosphohexoisomerase step (Wick et al. 1957).

However, by assuming that a feeding-inducing stimulus is generated during intramitochondrial oxidative phosphorylation and ATP production (Friedman 1991), the theory must also sustain that such a stimulus is independent of the type of fuel used during oxidation. Therefore, one would predict an enhanced effect on food intake when metabolism of more than one type of fuel is inhibited (since by blocking only one type of fuel metabolism the others are left to operate as alternative fuel reserves). In fact, Friedman and Tordoff (1986) have shown that 2-DG and methyl palmoxirate, an inhibitor of fatty acid oxidation at the membrane transport level, act synergistically to alter food intake in rats.

The above raises the question of how changes in fuel oxidation can be detected by the nervous system in order to ultimately alter food intake. Friedman et al. proposed that such fuel-oxidative information could be conveyed to the brain via afferent hepatic nerves, including the hepatic branch of the vagus (Friedman 1991). In fact, liver functions are not limited to simultaneously handling metabolic processes related to several different fuels (fatty acid oxidation and synthesis, metabolizing of fructose and glycerol, glycogen synthesis/breakdown, etc.; Langhans, Egli, and Scharrer 1985b). In addition, manipulations of hepatic metabolism seem to affect food intake patterns (Friedman et al. 1999) and interfere with normal feeding responses elicited by fructose intake (Langhans, Egli, and Scharrer 1985a). Furthermore, severing hepatic nerves alters normal food intake patterns (Friedman and Sawchenko 1984), suggesting that these nerves constitute a neural route through which information about fuel oxidation levels is relayed to brain circuits.

However, as noted by Friedman (1991) himself, there is no evidence that these lesions are selective to afferent fibers. Therefore, it could be assumed that at least part of this effect might result from an inability of the brain (as the ultimate sensor of energy status via hormonal factors) to control fuel metabolism in the liver. In fact, severing of hepatic nerves does not seem to abolish some compensatory intake behaviors that follow deprivation in rats (Egli, Langhans, and Scharrer 1986). One possibility is that fuel utilization, in this case glucose utilization, controls food intake via direct sensing by neurons, since brain cells require relatively high levels of glucose to preserve cellular function. In summary, although the idea that hepatic fuel oxidation relates to a peripheral signal that is conveyed to the brain to ultimately control feeding is an exciting hypothesis, research is needed in order to further our understanding on how information on fuel oxidation occurring at the mito-chondrial level ultimately reaches brain centers involved in postingestive-based control of feeding. Brain Sensing of Plasma Circulating Factors

Plasma levels of factors released in the bloodstream in response to nutrient intake could provide the brain with a reinforcement signal via activation of nerve afferents, such as the abdominal branches of the vagus in the case of cholecystochinin (CCK), or by binding to their respective specific receptors expressed in the brain, as in the case of adiposity factors such as insulin and leptin.

The intestinal satiety factor CCK has been shown to produce conditioned flavor preferences in rats (Perez and Sclafani 1991), suggesting a role for this factor in conditioned food preferences. However, the same group has also shown that high doses of the CCK-A receptor antagonist devaz-epide fail to inhibit flavor preferences conditioned by intraduodenal Polycose infusions (Perez, Lucas, and Sclafani 1998). Therefore, it appears that CCK-related mechanisms might be more directly related to the satiating effects of intraintestinal infusions of carbohydrates rather than to their postingestive reinforcing effects.

The pancreatic factor insulin is released in the bloodstream in response to nutrient intake. Peripherally circulating insulin crosses the blood-brain barrier in proportion to serum insulin levels via a saturable transport mechanism (Margolis and Altszuler 1967; Woods and Porte 1977). In 1979, Woods and colleagues showed that insulin infusions into the ventricular system of the brain result in reduced food intake and body weight (Woods et al. 1979). In fact, insulin receptors were soon after found to be richly expressed in the arcuate nucleus of the hypothalamus (Van Houten et al. 1979). In this nucleus, which is of central importance to food intake control, insulin receptors co-express with the anorexigenic neuropeptides proopiomelanocortin, the precursor of melanocyte-stimulating hormone, and cocaine- and amphetamine-regulated transcripts, as well as with the orexigenic neural factors neuropeptide Y and agouti-related peptide (Plum, Belgardt, and Bruning 2006).

One would thus expect that insulin could provide the brain with a signal conveying information on the processing of nutrients in the gut. In fact, a role for insulin in postingestive reinforcement has been suggested by the findings of Oetting, Vanderweele and colleagues. Vanderweele et al. (1985) showed that sham-feeding rats have the ability to acquire preferences for flavored milks that have been paired with insulin injection over flavored milks paired with saline injections. This however has been put into question by an experiment performed by Ackroff, Sclafani, and Axen (1997), who showed that rats treated with streptozotocin (a drug model of insulin-deficient diabetes) display the same behaviors as normal rats by preferring a flavor that had been mixed with a glucose solution over a flavor that had been mixed with a fructose solution. In addition, both diabetic and non-diabetic rats acquired a preference for the flavor paired with intragastric infusions of glucose over flavors paired with fructose infusions. These results would indicate that normal insulin responses to glucose are not necessary for glucose-conditioned flavor preference. Brain Dopamine Signaling

Conditioned preferences for caloric foods might also depend on brain-derived signals that are known to be involved in associations between unconditioned and conditioned reward stimuli. In fact, a role for dopamine signaling in flavor-nutrient conditioning is suggested by experiments employing administration of dopamine receptor antagonists in the nucleus accumbens. Rats treated with local infusions in nucleus accumbens of the D1-receptor antagonist displayed a dose-dependent reduction in intake of a flavor paired with intragastric infusions of glucose, compared with controls infused with saline (Touzani, Bodnar, and Sclafani 2008). Interestingly, the effect of dopamine signaling antagonism on postconditioning preference tests was less compelling. In any event, these results demonstrate that D1-like receptors in the nucleus accumbens are required for the acquisition, and possibly also for the expression, of glucose-conditioned flavor preferences.

One function that might be performed by dopamine signaling in accumbens during flavor-nutrient pairing is the strengthening of the associative link between conditioned flavors and unconditioned postingestive rewarding effects. It has in fact been proposed that the adaptive properties of increased accumbal dopamine release during taste stimulation are consistent with a role in associative learning (Di Chiara and Bassareo 2007). These authors have therefore proposed, consistent with the above, that release of dopamine in the nucleus accumbens, particularly in its more medial aspects (shell), following food intake might function to associate the gustatory properties of foods with their postingestive effects (Di Chiara and Bassareo 2007).

However, more recent findings suggest that the presence of taste or flavor stimulation is not required for the postingestive effects of foods to induce dopamine release in the nucleus accumbens. In fact, it has been found that in sweet-blind trpm5 knockout mice, caloric intake per se, independently of taste, was sufficient to increase extracellular dopamine levels in the nucleus accumbens (de Araujo et al. 2008). More precisely, it was first found in this study that the non-caloric sweetener sucralose intake produced significantly higher increases in dopamine levels in wild-type compared to knockout animals. These results are consistent with a role for dopamine signaling in accumbens derived from taste stimulation alone (Hajnal, Smith, and Norgren 2004). However, when the same comparison was performed with respect to sucrose, no differences were found between the dopamine release levels in wild-type and knockout mice. In other words, while sweet taste stimulation without caloric content produced, as expected, significant increases in accumbal dopamine levels in wild-type, taste-enabled animals but not in sweet-blind mice, caloric sucrose evoked the same levels of dopamine increase in both wild-type and knockout mice. These results therefore strongly suggest that even in the absence of taste transduction and/or palatability, nutrient intake has the ability to induce measurable tonic increases in accumbens dopamine. Thus palatability and postingestive factors both seem to increase dopamine levels independently in brain-reward circuits, though the nutrient-induced increases do not require the concomitant presence of flavor inputs, as had been suggested previously (Di Chiara and Bassareo 2007). It should be therefore inferred that events initiating in the gastrointestinal tract, most likely postabsorptive ones, regulate dopamine release in nucleus accumbens.

It remains unclear whether the same dopaminergic neurons are stimulated by these two independent pathways. If so, dopamine neurons would function within a brain circuit supporting the convergence of sensory (taste) and postingestive factors, possibly allowing for the formation of associations between them. Immunohistochemical and tracing techniques might be combined in future studies to determine whether dopamine neurons activated by metabolic cues are also targeted by taste projections from gustatory relays in the brainstem.

Whatever the mechanism inducing the dopaminergic rise in nucleus accumbens might be (i.e., flavor independent or not), neither of these two conjectures explains how postingestive factors gain access to midbrain dopamine cells in the first place. Some clues in this direction have been provided by the work by Figlewicz and colleagues, who have shown that the functional forms of the insulin and leptin receptors (Figlewicz et al. 2003), as well as of some of their substrates (Pardini et al. 2006), are richly expressed in dopaminergic neurons of the substantia nigra compacta and ventral tegmental area regions of the midbrain.

In fact, it has been demonstrated that leptin receptors expressed in dopaminergic neurons of the midbrain are functional and influence dopamine release (Fulton et al. 2006; Hommel et al. 2006). However, it is currently unknown whether brain leptin receptors play a role in postingestive reinforcement. In addition, the functional implications of insulin receptor expression in dopamine neurons have been little explored. Although it has been suggested that insulin infusions in the midbrain dopamine areas “decrease” the reward value of sucrose, since mice were found to reduce overall intake of sucrose solutions upon infusion (Figlewicz 2003; Figlewicz et al. 2006), this might simply imply that insulin receptor activation in midbrain dopamine areas provides the brain with a robust signal of caloric intake. In fact, if insulin were to decrease the reward value of foods, then we would expect that strongly insulin-releasing factors such as sugars or fats will become non-preferred over longer periods of time, which is obviously not the case. One interesting experiment testing the reinforcing power of insulin would consist of pairing non-caloric flavors with midbrain infusions of either insulin or vehicle and assessing their effects in postconditioning preference tests. An alternative explanation to the intriguing idea that brain insulin signaling decreases the reward value of sweet compounds consists in predicting that animals will develop a preference for flavors paired with insulin infusions. Although this would conflict with the results mentioned above stating that diabetic rats do display normal preferences for flavors associated with nutrients (Ackroff, Sclafani, and Axen 1997), it cannot be ruled out that diabetic rats might have developed compensatory mechanisms to low insulin levels, such as increases in plasma leptin. Therefore, the issue of whether brain insulin receptor signaling plays a role in postingestive reinforcement, and whether it interacts with leptin receptor signaling, remains open for future investigations.

Finally, another mechanism through which dopamine neurons could sense changes in physiological state refers to the possibility that dopamine neurons functions as glucosensors, i.e., that midbrain dopamine neurons can change their membrane potentials as a function of extracellular concentrations of glucose. It is currently unknown whether dopamine neurons express the cellular elements that seem to act as glucosensors in brain regions regulating energy homeostasis, such as the hypothalamus. For example, it would be interesting to verify whether glucokinase (hexokinase IV), which is the rate-limiting kinase in glucosensing (Levin 2006), is expressed in midbrain dopamine neurons, or whether dopamine neurons receive direct inputs from glucosensing neurons of the hypothalamus or brainstem.

In summary, it seems plausible that postingestive mechanisms operating as reinforcers in conditioned food preferences are of a postabsorptive nature, and most likely depend on signals that derive from fuel utilization (Figure 12.3). As we will see below, new research endeavors are needed to unveil the metabolic and central pathways involving the action of a postingestive reinforcement signal.

FIGURE 12.3. Putative pathways through which postingestive effects produced by eating nutrients might modulate dopamine activity and reward.


Putative pathways through which postingestive effects produced by eating nutrients might modulate dopamine activity and reward. Peripheral physiological signals generated by the ingestion of nutrients might gain access to the brain and modulate neural (more...)


In this chapter, we have argued that food reward consists of a multi-layered behavioral process, in which positive controls on intake are exerted by both proximal cues (with respect to eating, e.g., food flavor, the consummatory act) and distal cues (e.g., preingestive food-predictive signals, and postingestive physiological and metabolic effects). In short-term experiments performed on naïve animals, proximal cues seem to exert a stronger influence on intake. However, the bulk of evidence from past and current studies favors the view that the critical event regulating preferences for certain nutrients over others across extended periods of time consist primarily of postingestive effects. Furthermore, the postingestive effects relevant for the formation of conditioned food preferences seem to be of a postabsorptive nature, i.e., they seem to depend on fuel utilization/oxidation and/ or hormonal release. Finally, these behaviorally critical postabsorptive effects have been shown to activate brain reward pathways, including the mesolimbic brain dopamine system, an effect that does not depend on the concomitant presence of taste or flavor stimulation. In other words, although multiple layers of rewarding influences affect food intake, a hierarchy exists in which palatable compounds unable to provide sources for fuel oxidation eventually become less preferred in comparison to more energy-rich sources. From a biological point of view, a postingestive reinforcement signal that depends on postabsorptive events obviously provides great advantages over hypothetical preabsorptive mechanisms.

However, several crucial questions remain to be addressed concerning the identity and nature of the postingestive reinforcement signal. If on one hand the early observations by Adolph (1947) suggesting that animals “eat for calories” remain essentially correct, it remains to be demonstrated that different fuels providing the same amount of calories per gram will produce the same postingestive reinforcement effect. In fact, depending on the identity of the body part that turns out to be the crucial generator of postingestive reward signals, certain macronutrients might be more prone to act as postingestive reinforcers than others due to the intrinsic differences in how organs metabolize fuels.

For example, whereas several peripheral organs can make efficient usage of non-glucose fuels such as fatty acids, brain cells rely almost entirely on glucose or its immediate derivatives including lactate (Bouzier-Sore et al. 2006; Oltmanns et al. 2008; Pellerin 2008). This is consistent with the significant increases in feeding observed following inhibition of glucose utilization in the brain (Miselis and Epstein 1975). In addition, it is revealing that in one study, infusions of fatty acid oxidation inhibitors induced increases in food intake only upon co-administration with a glucose utilization inhibitor (Friedman and Tordoff 1986). These results favor the hypothesis that a crucial aspect of food reinforcement relates to glucose utilization and oxidation. Therefore, due to the critical reliance of the brain on glucose, it is plausible to hypothesize that glucose metabolism in brain cells is required for the generation of behaviorally relevant postingestive reward signals. Of particular interest is whether the blockage of glucose utilization in midbrain dopamine regions is sufficient to disrupt the formation of food preferences based on postingestive effects. Future research must determine the extent to which dopamine neurons of the brain reward pathways operate as true metabolic sensors, and whether metabolic sensing can influence dopamine-associated functions such as temporal difference learning and reward prediction (Hollerman and Schultz 1998; also see Chapters 14 and 15 in this volume).

It must be observed that none the of physiological mechanisms that might plausibly function as postingestive reward signals can offer an explanation for how the brain forms associations between sensory information that arises from flavor inputs and ensuing metabolic events taking place several minutes or even hours later. Although research on this topic remains to be undertaken, experiments involving aversive postingestive effects including conditioned taste aversion paradigms suggest that gustatory cortical circuits might play a fundamental role in actively sustaining sensory information in order to allow the formation of neural associations with ensuing postingestive effects (Berman and Dudai 2001). The precise role of the gustatory cortex in the regulation of postingestive reinforcement is yet another important topic for future investigation.

As a final comment, while the research presented here has overwhelmingly focused on vertebrate species, this should not be taken to imply that food reward research is limited to these organisms. On the contrary, the involvement of dopamine and other amines in reward and punishment signaling is equally important for invertebrate species. In insects such as Apis mellifera, Gryllus bimaculatus, and Drosophila melanogaster, the two biogenic amines dopamine and octopamine seem to be involved in punishment and reward learning, respectively (Schwaerzel et al. 2003; Unoki, Matsumoto, and Mizunami 2005; Selcho et al. 2009). More recently, it has been suggested that dopamine signaling via the dD1 receptor is essential for both reward and aversive processing in Drosophila (Kim, Lee, and Han 2007). Altogether, the current evidence suggests conserved dopaminergic mechanisms for reward processing across different species. In addition, the Drosophila analogue of the mammalian tyrosine hydroxylase enzyme catalyzes the rate-limiting step of dopamine synthesis and is expressed in all dopaminergic neurons (Friggi-Grelin et al. 2003), a finding that further indicates conserved mechanisms in reward learning. Future research must determine whether, in addition to olfactory cues conditioned to primary rewards, gustatory inputs and/or changes in physiological state have the ability to regulate dopamine release in Drosophila. In any event, the presence of dopamine-dependent reward processing in Drosophila reveals the opportunity for thorough investigations of the molecular bases of dopaminergic system sensitivity to metabolic cues.


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In this chapter the terms “palatable” and “palatability” will refer to the orosensory rewarding properties of a stimulus that are sufficient to elicit intake independently of learning or previous experience. Although some authors favor using this term as relating to the overall set of factors exerting positive controls on intake, we would like in the present chapter to exclude from the definition of “palatable” those initially unpleasant compounds, such as mild irritants or bitter tastants, which might gain incentive value through association with postingestive effects.


It must be noted that the involvement of dopamine and other amines in reward and punishment signaling is not restricted to mammalian species. In particular, Drosophila larvae are capable of forming aversive and appetitive associations between odorant and gustatory cues (Gerber and Stocker 2007), an ability that seems to depend on the two biogenic amines dopamine and octopamine respectively (Schwaerzel et al. 2003). However, because it remains unclear whether nutrients can directly stimulate amine neurons in insects, in this chapter we will restrict the discussion to data obtained efrom higher, mammalian animals. See Section 12.4 for further discussion.


It must be noted that the existence of gustatory labeled lines in the periphery does not allow one to conclude that distributed encoding is not involved in representing taste information in the central nervous system. In fact, it seems that the intricate circuitry of the brain allows for taste information to be encoded by entire populations of non-sensory specific neurons (Katz, Simon, and Nicolelis 2001), and such representations might even involve precise temporal patterns of firing activity (Di Lorenzo 2003).


In primates, the parabrachial nucleus does not seem to integrate the central taste pathways, with solitary tract fibers projecting directly onto the taste portion of the thalamus (Scott and Small 2009). Thus the relationship between taste-induced dopamine release and the parabrachial nucleus remains to be determined in primate models.

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