Intraoral Infusion Of Sucrose Research Articles

Mode of Sucrose Delivery Alters Reward-Related Phasic Dopamine Signals in Nucleus Accumbens.

In studies of appetitive Pavlovian conditioning, rewards are often delivered to subjects in a manner that confounds several processes. For example, delivery of a sugar pellet to a rodent requires movement to collect the pellet and is associated with sensory stimuli such as the sight and sound of the pellet arrival. Thus, any neurochemical events occurring in proximity to the reward may be related to multiple coincident phenomena. We used fast-scan cyclic voltammetry in rats to compare nucleus accumbens dopamine responses to two different modes of delivery: sucrose pellets, which require goal-directed action for their collection and are associated with sensory stimuli, and intraoral infusions of sucrose, which are passively received and not associated with external stimuli. We found that when rewards were unpredicted, both pellets and infusions evoked similar dopamine release. However, when rewards were predicted by distinct cues, greater dopamine release was evoked by pellet cues than infusion cues. Thus, dopamine responses to pellets, infusions as well as predictive cues suggest a nuanced role for dopamine in both reward seeking and reward evaluation.

State-dependent value representation: evidence from the striatum.

State-dependent value representation: evidence from the striatum.

Encoding of Aversion by Dopamine and the Nucleus Accumbens

Adaptive motivated behavior requires rapid discrimination between beneficial and harmful stimuli. Such discrimination leads to the generation of either an approach or rejection response, as appropriate, and enables organisms to maximize reward and minimize punishment. Classically, the nucleus accumbens (NAc) and the dopamine projection to it are considered an integral part of the brain’s reward circuit, i.e., they direct approach and consumption behaviors and underlie positive reinforcement. This reward-centered framing ignores important evidence about the role of this system in encoding aversive events. One reason for bias toward reward is the difficulty in designing experiments in which animals repeatedly experience punishments; another is the challenge in dissociating the response to an aversive stimulus itself from the reward/relief experienced when an aversive stimulus is terminated. Here, we review studies that employ techniques with sufficient time resolution to measure responses in ventral tegmental area and NAc to aversive stimuli as they are delivered. We also present novel findings showing that the same stimulus – intra-oral infusion of sucrose – has differing effects on NAc shell dopamine release depending on the prior experience. Here, for some rats, sucrose was rendered aversive by explicitly pairing it with malaise in a conditioned taste aversion paradigm. Thereafter, sucrose infusions led to a suppression of dopamine with a similar magnitude and time course to intra-oral infusions of a bitter quinine solution. The results are discussed in the context of regional differences in dopamine signaling and the implications of a pause in phasic dopamine release within the NAc shell. Together with our data, the emerging literature suggests an important role for differential phasic dopamine signaling in aversion vs. reward.

Control of appetitive and aversive taste-reactivity responses by an auditory conditioned stimulus in a devaluation task: a FOS and behavioral analysis.

Through associative learning, cues for biologically significant reinforcers such as food may gain access to mental representations of those reinforcers. Here, we used devaluation procedures, behavioral assessment of hedonic taste-reactivity responses, and measurement of immediate-early gene (IEG) expression to show that a cue for food engages behavior and brain activity related to sensory and hedonic processing of that food. Rats first received a tone paired with intraoral infusion of sucrose. Then, in the absence of the tone, the value of sucrose was reduced (Devalue group) by pairing sucrose with lithium chloride (LiCl), or maintained (Maintain group) by presenting sucrose and LiCl unpaired. Finally, taste-reactivity responses to the tone were assessed in the absence of sucrose. Devalue rats showed high levels of aversive responses and minimal appetitive responses, whereas Maintain rats exhibited substantial appetitive responding but little aversive responding. Control rats that had not received tone-sucrose pairings did not display either class of behaviors. Devalue rats showed greater FOS expression than Maintain rats in several brain regions implicated in devaluation task performance and the display of aversive responses, including the basolateral amygdala, orbitofrontal cortex, gustatory cortex (GC), and the posterior accumbens shell (ACBs), whereas the opposite pattern was found in the anterior ACBs. Both Devalue and Maintain rats showed greater FOS expression than control rats in amygdala central nucleus, GC, and both subregions of ACBs. Thus, through associative learning, auditory cues for food gained access to neural processing in several brain regions importantly involved in the processing of taste memory information.

Infantile Sensitivity to Ethanol's Motivational Effects: Ethanol Reinforcement During the Third Postnatal Week

Although tests specific to newborn rats have frequently verified their susceptibility to the reinforcing properties of ethanol, demonstration of comparable reinforcing effects in older infants has been elusive. Using a second-order conditioning procedure, the present study assessed in preweanling rats whether pairing with early postabsorptive effects of ethanol would render intraorally delivered gustatory stimuli capable of positive reinforcement for association with a salient texture. Direct reinforcing effects of ethanol were also evaluated through intake tests of gustatory stimuli previously paired with the drug. Blood ethanol levels (BELs) were determined for each of the ethanol doses used. Pups (14 days old) were stimulated with intraoral infusion of sucrose (10% v/v), water, or quinine (0.0045% w/v) 5 minutes after being intragastrically (i.g.) administered 0.00, 0.25, 0.50, or 2.00 g/kg ethanol (Experiments 1 and 2). These stimuli were then briefly presented while pups experienced a rough texture (sandpaper). Rats were subsequently evaluated in a 2-way texture location test (sandpaper vs smooth surface). In Experiment 3, sucrose, water, or quinine was paired with early postabsorptive effects of ethanol (0.00, 0.50, or 2.0 g/kg). Consumption of these stimuli was later assessed. Motor activity patterns during the intake test were also evaluated. In Experiment 4, BELs corresponding to 0.25, 0.50, or 2.0 g/kg ethanol were determined 5 and 20 minutes after i.g. administration (time periods were in accord with the onset and offset of intraoral stimulation used in the previous experiments). Intraoral infusion of sucrose, water, or quinine, while under a state of sobriety and paired with sandpaper, resulted in roughly 50% preference for this texture. Sandpaper preferences were significantly elevated in pups that had experienced sucrose or water in a nonsober state-while under the effects of ethanol (Experiments 1 and 2). This indicated reinforcing effects of the ethanol intoxication. Pairing ethanol intoxication directly with consumption of sucrose, water, or quinine did not affect their later consumption. Yet, there were clear indications that this pairing resulted in conditioned behavioral activity patterns. Blood ethanol levels corresponding to the ethanol doses used here ranged between 10 and 150 mg%. Infants appear sensitive to pharmacological reinforcing properties of low and relatively high ethanol doses. This sensitivity was revealed indirectly, by pairing gustatory stimuli with ethanol intoxication and then allowing these stimuli to act as second-order reinforcement for a quite different (tactile) stimulus. Behavioral activation elicited by the gustatory stimuli previously paired with a state of intoxication seems to compete with the expression of ethanol's motivational properties as assessed through intake tests.

Nucleus Accumbens Neurons Are Innately Tuned for Rewarding and Aversive Taste Stimuli, Encode Their Predictors, and Are Linked to Motor Output

The nucleus accumbens (NAc) is a key component of the brain's reward pathway, yet little is known of how NAc cells respond to primary rewarding or aversive stimuli. Here, naive rats received brief intraoral infusions of sucrose and quinine paired with cues in a classical conditioning paradigm while the electrophysiological activity of individual NAc neurons was recorded. NAc neurons (102) were typically inhibited by sucrose (39 of 52, 75%) or excited by quinine (30 of 40, 75%) infusions. Changes in firing rate were correlated with the oromotor response to intraoral infusions. Most taste-responsive neurons responded to only one of the stimuli. NAc neurons developed responses to the cues paired with sucrose and quinine. Thus, NAc neurons are innately tuned to rewarding and aversive stimuli and rapidly develop responses to predictive cues. The results indicate that the output of the NAc is very different when rats taste rewarding versus aversive stimuli.

Age-dependency of analgesia elicited by intraoral sucrose in acute and persistent pain models

Treatment of pain in newborns is associated with problematic drug side effects. Previous studies demonstrate that an intraoral infusion of sucrose and other sweet components of mother's milk are effective in alleviating pain in infant rats and humans. These findings are of considerable significance, as sweet tastants are used in pain and stress management in a number of clinical procedures performed in human infants. The ability of sweet stimuli to induce analgesia is absent in adult rats, suggesting that this is a developmentally transient phenomenon. However, the age range over which intraoral sucrose is capable of producing analgesia is not known. We investigated the effects of intraoral sucrose (7.5%) on nocifensive withdrawal responses to thermal and mechanical stimuli in naive and inflamed rats at postnatal days (P) P0–21. In some rats, Complete Freund's adjuvant (CFA) was injected in a fore- or hindpaw to produce inflammation. In non-inflamed animals, for noxious thermal stimuli, sucrose-induced analgesia emerged at P3, peaked at P7–10, then progressively declined and was absent at P17. For mechanical forepaw stimuli, sucrose-induced analgesia emerged, and was maximal at ∼P10, then declined and was absent at P17. By contrast, maximal sucrose-induced analgesia for mechanical hindpaw stimuli was delayed (P13) compared to that for the forepaw, although it was also absent at P17. In inflamed animals, sucrose reduced hyperesthesia and hyperalgesia assessed with mechanical stimuli. Sucrose-induced analgesia in inflamed animals was initially present at P3 for the forepaw and P13 for the hindpaw, and was absent by P17 for both limbs. Intraoral sucrose produced significantly greater effects on responses in fore- and hindpaws in inflamed rats than in naive rats indicating that it reduces hyperalgesia and allodynia beyond its effects on responses in naive animals. These findings support the hypothesis that sucrose has a selective influence on analgesic mechanisms and that an enhanced sucrose effect takes place in hyperalgesic, inflamed animals as compared to naive animals. Taken together, these results indicate that intraoral sucrose alleviates transient pain in response to thermal and mechanical stimuli, and also effectively reduces inflammatory hyperalgesia and allodynia. Sucrose-induced analgesia is age-dependent and limited to the pre-weaning period in rats. The age-dependency of sucrose-induced analgesia and its differential maturation for the fore- and hindpaw may be due to developmental changes in endogenous analgesic mechanisms and developmental modulation of the interaction between gustatory and pain modulatory pathways.

Aversive behavior during intraoral intake in male rats

We investigated if the taste of a sucrose solution becomes progressively more aversive during intraoral infusion and if this contributes to the termination of the intake in male rats. The display of aversive behavior, such as gapes and chin rubs, but not headshakes, forelimb flails or orofacial grooming, varied with the concentration of an intraorally infused solution of quinine hydrochloride (QHCl) and increased by the time the rat rejected an intraorally infused 2 M solution of sucrose. Activation of gapes and chin rubs by brief intraoral infusion of QHCl advanced the rejection of the sucrose solution if given late during intraoral infusion, but blockade of gaping by anaesthesization of the oral cavity with Xylocain did not prolong the intake of the sucrose solution. Headshakes and forelimb flails could be elicited by stimulating the head and limbs with sucrose, and gapes and chin rubs were activated by infusion of a 2 M solution of sucrose into the stomach or duodenum but not by infusion of glucose into the jugular or hepatic portal vein. Preventing filling of the gastrointestinal tract during intraoral infusion of sucrose (sham feeding) eliminated the display of gapes and chin rubs. It is suggested that an increase in the aversiveness of the taste of a sucrose solution contributes to the rejection of that solution during intraoral infusion. However, rats can reject a sucrose solution in the absence of any behavioral sign of aversion and none of the so-called “taste-related” aversive behaviors is exclusively dependent upon stimulation of the taste receptors in the oral cavity.

Differential effects of lipopolysaccharide and cholecystokinin on sucrose intake and palatability.

The differential effects of CCK and lipopolysaccharide (LPS) on sucrose intake and palatability were examined. Rats were injected with LPS (200 microg/kg ip) or NaCl (0.9%, vehicle) and 2 h later received a second injection of either CCK (8 microg/kg ip) or NaCl. In experiment 1, sucrose (0.3 M) intake was monitored for 1 h on three different test days 72 h apart, while in experiment 2, palatability was assessed by means of the taste reactivity test (TRT) on two separate days (72 h apart). In the TRT, orofacial and somatic responses to brief (30 s) intraoral infusions of sucrose were recorded and analyzed for response frequency. Singly, LPS and CCK reduced sucrose intake, with a more pronounced effect from combined LPS and CCK. LPS by itself did not alter sucrose palatability, as evidenced by continuous high levels of ingestive responding. In contrast, CCK-treated rats displayed a pattern of responding indicative of satiety, as did the combined LPS-CCK-treated rats. These results suggest that LPS does not induce hypophagia by altering palatability.

Rapid, Labile, and Protein Synthesis– Independent Short-Term Memory in Conditioned Taste Aversion

Short-term memory is a rapid, labile, and protein-synthesis-independent phase of memory. The existence of short-term memory in conditioned taste aversion (CTA) learning has not been demonstrated formally. To determine the earliest time at which a CTA is expressed, we measured intraoral intake of sucrose at 15 min, 1 hr, 6 hr, or 48 h after contingent pairing of an intraoral infusion of 5% sucrose (6.6 ml over 6 min) and toxic lithium chloride injection (76 mg/kg). Rats were implanted with intraoral catheters to allow presentation of taste solutions at arbitrary times. Intraoral intake was measured under conditions of long-delay, single-trial learning typical of CTA. Rats decreased intraoral intake of sucrose at 15 min after contingent pairing of sucrose and LiCl, but not after noncontingent LiCl or sucrose. Thus CTA learning can be expressed rapidly. To determine if short-term CTA memory is labile and decays in the absence of long-term memory, we measured intraoral intake of sucrose after pairing sucrose with low doses of LiCl. Rats received an intraoral infusion of 5% sucrose (6 ml/6 min); 30 min later LiCl was injected at three different doses (19, 38, or 76 mg/kg). A second intraoral infusion of sucrose was administered 15 min, 1 hr, 3 hr, 4.5 hr, 6 hr, or 48 hr later. The formation of long-term CTA memory was dependent on the dose of LiCl paired with sucrose during acquisition. Low doses of LiCl induced a CTA that decayed within 6 hr after pairing. Central administration of the protein synthesis inhibitor cycloheximide prior to LiCl injection blocked long-term CTA expression at 6 and 48 hr, but not short-term CTA expression at 1 hr. Thus, short-term memory for CTA learning exists that is acquired rapidly and independent of protein synthesis, but labile in the absence of long-term memory formation.

Gustatory and visceral inputs to the amygdala of the rat: conditioned taste aversion and induction of c- fos-like immunoreactivity

Expression of proto-oncogene c- fos was immunohistochemically examined in the central and basolateral amygdaloid nuclei in rats after ingestion of taste solutions (0.5 M sucrose or 0.005 M saccharin), intragastric infusion of these solutions, or an intraperitoneal injection of malaise-inducing lithium chloride (LiCl). c- Fos-like immunoreactive neurons were distributed most densely in the central nucleus in response to the LiCl injection, followed by the ingestion and intragastric infusion of sucrose. The intraoral infusion of sucrose, but not of saccharin, elicited intense c- fos expression in the central nucleus after establishment of conditioned taste aversion to these taste stimuli. The results are discussed in terms of post-ingestional factors and the conditioned illness reaction after taste aversion learning.

C-Fos Induction in the Rat Nucleus of the Solitary Tract by Intraoral Quinine Infusion Depends on Prior Contingent Pairing of Quinine and Lithium Chloride

Intraoral infusions of sucrose or saccharin induce c-Fos-like immunoreactivity (c-FLI) in the intermediate nucleus of the solitary tract (iNTS) of rats after acquisition of a conditioned taste aversion (CTA). The induction of c-FLI in the iNTS may be a consequence of the shift in behavioral response from ingestive to aversive behaviors that characterize acquisition and expression of a CTA. To test this hypothesis, rats were intraorally infused with 0.3 mM quinine sulfate, an aversive taste, 1. prior to conditioning, 2. after 3 noncontingent (unpaired) infusions of quinine and toxic lithium chloride (LiCl) injections, 3. after conditioning with 3 contingent pairings of quinine and LiCl, and 4. after extinction with repeated unpaired infusions of quinine. Intraoral infusions of quinine induced c-FLI in the iNTS only after acquisition of a CTA against quinine; quinine failed to induce c-FLI in the iNTS of unconditioned, noncontingently treated, or extinguished rats. The pattern of c-FLI in the iNTS induced by expression of a CTA against quinine was quantitatively and anatomically similar to that elicited by sucrose in rats expressing a CTA against sucrose. We conclude that aversive responses per se are not sufficient to induce c-FLI in the iNTS. Furthermore, contingent pairing of quinine and LiCl does not cause a shift in behavioral response from palatable, ingestive behaviors to aversive behaviors as in acquisition of a CTA against sucrose. Thus, we also conclude that a shift in behavior from ingestive to aversive responses is not required for increased c-FLI expression in the iNTS during CTA expression. Therefore, the induction of c-FLI in the iNTS during expression of a CTA may be correlated with neuronal processes specific to acquisition and expression of a CTA.

Toxin-induced conditioned changes in taste reactivity and the role of the chemosensitive area postrema

Conditioned taste avoidances (CTAs) are an important component of behavioral regulation of ingestion. In the laboratory CTAs can be produced by pairing a novel taste stimulus with the physiological feedback produced by a toxin, such as lithium. Such toxins putatively activate a chemosensitive brainstem structure, the area postrema, which ultimately results in the production of a CTA. The present review describes a series of studies which examined conditioned changes in taste reactivity responses (TRRs) when a novel intraoral sucrose taste was paired with the effects of an intraperitoneal (IP) injection of LiCl, and the role of the area postrema in the formation of conditioned palatability shifts. It was first of all necessary to examine the effects of area postrema ablations on TRRs to a range of intraoral sucrose and quinine stimulus intensities. In the first study area postrema lesioned rats exhibited concentration dependent changes in TRRs to these taste stimuli that were very similar to those exhibited by sham lesioned rats. The second study demonstrated that 30 s intraoral infusions of sucrose (0.3 M), presented at 5 or 10 min intervals following an IP injection of LiCl (3.0 meq), resulted in conditioned changes in TRRs. These were characterized by orderly, gradual reductions in ingestive responses and increases in aversive responses. Finally, when area postrema lesioned rats (Study 3) were subjected to this conditioning procedure (brief sucrose presentations paired with the effects of LiCl) no evidence for conditioned or unconditioned changes in TRRs to sucrose were obtained. Lesioned rats injected with LiCl behaved similarly to sham lesioned rats injected with NaCl. These series of studies provide evidence indicating that the chemosensitive area postrema mediates the formation of conditioned palatability shifts induced by treatment with a toxin such as lithium.

Opioid mediation of odor preferences induced by sugar and fat in 6-day-old rats

Intraoral infusions of sucrose, fat or polycose reduce ultrasonic vocalizations during isolation, and increase pain threshold in infant rats. These effects are naltrexone reversible. The present study determined whether these substances, when paired with an odor, caused a change in preference for that odor. In 6-day-old rats, pairing orange odor with intraoral infusions of sucrose or corn oil, but not polycose, water, mineral oil or 0.01% quinine hydrochloride, caused a substantial increase in preference for orange. Preference formation was blocked by systemic injection of naltrexone (0.25 mg/kg) prior to pairing orange with either sucrose or corn oil. Moreover, preference expression was prevented by naltrexone injection prior to testing. Thus certain substances thought to reduce stress in infant rats via endogenous opioid release can also cause preference for substances that predict their occurrence. Preference formation depends upon the availability of endogenous opioids. Preference expression reflects the conditioned stimulus causing opioid release.