Rats avoid intake of a taste cue when paired with a drug of abuse or with the illness-inducing agent, lithium chloride (LiCl). Although progress has been made, it is difficult to compare the suppressive effects of abused agents and LiCl on intake of a gustatory conditioned stimulus (CS) because of the cross-laboratory use of different CSs, different unconditioned stimuli (USs), and different doses of the drugs, different conditioning regimens, and different restriction states. Here we have attempted to unify these variables by comparing the suppressive effects of a range of doses of morphine, cocaine, and LiCl on intake of a saccharin CS using a common regimen in non-restricted, food restricted, or water restricted male Sprague-Dawley rats. The results showed that, while the putatively aversive agent, LiCl, was effective in suppressing intake of the taste cue across nearly all doses, regardless of restriction state, the suppressive effects of both morphine and cocaine were greatly reduced when evaluated in either food or water restricted rats. Greater sensitivity to drug was revealed, at very low doses, when testing occurred in the absence of need (i.e., when the rats were non-restricted). Together, these results provide the first uniform and comprehensive analysis of the suppressive effects of morphine, cocaine, and LiCl as a function of dose and restriction state. In the present case, the suppressive effects of morphine and cocaine are found to differ from those of LiCl and, in some respects, from one another as well.

Rats suppress intake of a palatable taste cue when paired with a rewarding or an aversive stimulus in appetitive or aversive conditioning, respectively. A similar phenomenon occurs with drugs of abuse, but the nature of this conditioning has been subject for debate. While relatively little is known about the underlying neural circuitry, we recently reported bilateral lesions of the thalamic trigeminal orosensory area isolate drug-induced suppression of intake of a taste cue. The lesion blocks avoidance of the taste cue when paired with experimenter delivered drugs of abuse, yet has no effect on avoidance of the same cue when paired with an aversive agent or when it predicts access to a highly palatable sucrose solution. We hypothesize the lesion may blunt the rewarding properties of the drug. To test this, we used a runway apparatus, as running speed has been shown to increase with increasing reward value. Our hypothesis was supported by failure of the lesioned rats to increase running speed for morphine. Interestingly, lesioned rats did avoid intake of the drug-paired cue when presented in the runway apparatus and displayed naloxone-precipitated withdrawal. Using a partial crossover design, the lesion prevented avoidance of a cocaine-paired cue when presented in the home cage. We conclude that the lesion disrupts avoidance of a taste cue in anticipation of the rewarding properties of a drug but, at least in the presence of contextual cues, allows for avoidance of a taste cue as it elicits the onset of an aversive conditioned state of withdrawal.

Rats emit aversive taste reactivity (TR) behavior (i.e., gapes) following intraoral delivery of a cocaine-paired taste cue and greater conditioned aversive TR at the end of training predicts greater drug-seeking and taking. Here, we examined the development of this conditioned aversive TR behavior on a trial-by-trial basis in an effort to determine when the change in behavior occurs and whether early changes in this behavior can be used to predict later drug taking. The results show that conditioned aversive TR to a cocaine-paired cue occurs very early in training (i.e., following as few as 1-2 taste-drug pairings) and, importantly, that it can be used to predict later drug seeking and drug taking in rats.

We consider conditioned taste aversion to involve a learned reduction in the palatability of a taste (and hence in amount consumed) based on the association that develops when a taste experience is followed by gastrointestinal malaise. The present article evaluates the well-established finding that drugs of abuse, at doses that are otherwise considered rewarding and self-administered, cause intake suppression. Our recent work using lick pattern analysis shows that drugs of abuse also cause a palatability downshift and, therefore, support conditioned taste aversion learning.

Data have suggested that rats avoid intake of an otherwise palatable saccharin cue when paired with a drug of abuse, at least, in part, because the value of the taste cue pales in anticipation of the availability of the highly rewarding drug. Earlier support for this hypothesis was provided by the finding that, relative to the less sensitive Fischer rats, Lewis rats exhibit greater avoidance of a saccharin cue when paired with a rewarding sucrose or cocaine unconditioned stimulus (US), but not when paired with the aversive agent, lithium chloride. More recent data, however, have shown that Fischer rats actually exhibit greater, not less, avoidance of the same saccharin cue when morphine serves as the US. Therefore, Experiment 1 evaluated morphine-induced suppression of intake of the taste cue in Lewis and Fischer rats when the morphine US was administered subcutaneously, rather than intraperitoneally. Experiment 2 examined the effect of strain on the suppression of intake of the saccharin cue when paired with spiradoline, a selective kappa-opioid receptor agonist. The results confirmed that Fischer rats are more responsive to the suppressive effects of morphine than Lewis rats, and that Fischer rats also exhibit greater avoidance of the saccharin cue when paired with spiradoline, despite the fact that spiradoline is devoid of reinforcing properties. Taken together, the data suggest that the facilitated morphine-induced suppression observed in Fischer rats, compared with Lewis rats, may reflect an increased sensitivity to the aversive, kappa-mediated properties of opiates.

A unifying physiological explanation of the urge to initiate eating is still not available as human hunger in meal-to-meal eating may not be under homeostatic control. We hypothesized that a central circadian and a gastrointestinal ultradian timing mechanism coordinate non-deprivation meal-to-meal eating. We examined hunger as a function of time of day, inter-meal (IM) energy expenditure (EE), and concentrations of proposed hunger-controlling hormones ghrelin, leptin, and insulin.

In two crossover studies, 10 postmenopausal women, BMI 23-26 kg/m(2) engaged in exercise (EX) and sedentary (SED) trials. Weight maintenance meals were provided at 6h intervals with an ad libitum meal at 13 h in study 1 and 21 h snack in study 2. EE during IM intervals was measured by indirect calorimetry and included EX EE of 801 kcal in study 1, and 766-1,051 kcal in study 2. Hunger was assessed with a visual analog scale and blood was collected for hormonal determination.

Hunger displayed a circadian variation with acrophase at 13 and 19 h and was unrelated to preceding EE. Hunger was suppressed by EX between 10 and 16 h and bore no relationship to either EE during preceding IM intervals or changes in leptin, insulin, and ghrelin; however leptin reflected IM energy changes and ghrelin and insulin, prandial events.

During non-deprivation meal-to-meal eating, hunger appears to be under non-homeostatic central circadian control as it is unrelated to EE preceding meals or concentrations of proposed appetite-controlling hormones. Gastrointestinal meal processing appears to intermittently suppress this control and entrain an ultradian hunger pattern.

It is well established that female rats are more sensitive than male rats to the reinforcing effects of cocaine (Lynch, 2008 [42] for review). We hypothesized that greater preference for cocaine would support greater avoidance of a cocaine-paired taste cue in female vs. male rats. Moreover, at least in male rats, greater avoidance of the taste cue is associated with greater cocaine self-administration (Grigson and Twining, 2002 [3]). Thus, we anticipated that female rats would not only demonstrate greater avoidance of the drug-paired taste cue, but greater drug-taking as well. We tested these hypotheses by examining avoidance of a saccharin cue in male and female rats following several pairings with self-administered saline or cocaine (0.16, 0.33, or 0.66 mg/infusion). Contrary to expectations, the results showed that female rats exhibited less avoidance of the cocaine-associated saccharin cue than male rats and self-administered less, rather than more, cocaine, Thus, while female rats reportedly take more drug than male rats when the drug is presented in the absence of an alternative reward, they take less drug than male rats when the opportunity to self-administer cocaine is preceded by access to a palatable sweet. Females, then, may not simply be more sensitive to the rewarding properties of drug, but also to the reinforcing properties of natural rewards and this increase in sensitivity to sweets may serve to protect against drug-taking behavior.

Substance abuse and addiction are associated with an apparent devaluation of, and inattention to, natural rewards. This consequence of addiction can be modeled using a reward comparison paradigm where rats avoid intake of a palatable taste cue that comes to predict access to a drug of abuse. Evidence suggests rats avoid intake following such pairings, at least in part, because the taste cue pales in comparison to the highly rewarding drug expected in the near future. In accordance, lesions of the gustatory thalamus or cortex eliminate avoidance of a taste cue when paired with either a drug of abuse or a rewarding sucrose solution, but not when paired with the aversive agent, LiCl. The present study used bilateral ibotenic acid lesions to evaluate the role of a neighboring thalamic structure, the trigeminal orosensory area (TOA), in avoidance of a gustatory cue when paired with sucrose (experiment 1), morphine (experiment 2), cocaine (experiment 3), or LiCl (experiment 4). The results show that the TOA lesion disrupts, but does not eliminate avoidance of a taste cue that predicts access to a preferred sucrose solution and leaves intact the development of a LiCl-induced conditioned taste aversion. The lesion does, however, eliminate the suppression of intake of a taste cue when paired with experimenter-administered morphine or cocaine using our standard parameters. As such, this is the first manipulation found to dissociate avoidance of a taste cue when mediated by a sweet or by a drug of abuse.

One of the most menacing consequences of drug addiction is the devaluation of natural rewards (e.g. food, sex, work, money, caring for one's offspring). However, evidence also suggests that natural rewards, such as an enriched environment, can devalue drugs of abuse. Thus, this study used a rodent model to test whether exposure to an enriched environment could protect adult rats from acquiring cocaine self-administration and from the resultant drug-induced devaluation of a natural saccharin reward cue. Adult male Sprague-Dawley rats were implanted with intravenous jugular catheters. Rats were then separated into two housing conditions: an enriched condition, including social companions(four/cage) and novel objects (e.g. balls, polyethylene tubes, paper, etc.), and a nonenriched condition where the rats were singly housed with no novel objects. During testing, the rats were given 5-min access to 0.15% saccharin, followed by 1 h to self-administer saline or cocaine (0.167 mg/infusion) on fixed ratio and progressive ratio schedules of reinforcement. The results showed that rats that were singly housed in the nonenriched environment fell into two groups: low drug-takers (n=34) and high drug-takers (n=12). In comparison, only one out of the 22 rats housed in the enriched environment was a high drug-taker. Thus, all rats in the enriched environment, except one, behaved like low drug-takers under the nonenriched condition. As such, these rats self-administered almost no drug on either the fixed ratio or the progressive ratio schedule of reinforcement and were extremely slow to self-administer their first cocaine infusion. Interestingly, despite their very low levels of drug self-administration, low-drug-taking rats housed in the enriched environment continued to avoid intake of the drug-associated saccharin cue. Taken together, these data suggest that the enriched environment itself served as a salient natural reward that reduced cocaine seeking and cocaine taking, but had little impact on avoidance of the cocaine-paired taste cue. The protective effects of the enriched environment were robust and, as such, have important implications for the methods used in the study of drug addiction in animal models and for the prevention, and possibly the treatment, of the disease in adult humans.

Drugs of abuse are known to reduce intake of a taste conditioned stimulus (conditional stimulus, CS), a behavioral response sometimes seen as paradoxical because the same drugs also serve as rewards in other behavioral procedures. In the present study we compared patterns of intake and palatability (assessed using microstructural analysis of licking) for a standard saccharin CS paired with the following: lithium chloride, morphine, amphetamine, or sucrose. We found that morphine and amphetamine, like lithium-induced illness, each suppressed CS intake and caused a reduction in saccharin palatability. Sucrose, a rewarding stimulus, did not reduce the palatability of the saccharin CS. We interpret these finds as evidence that drugs of abuse induce conditioned taste aversions.

The present study investigated the role of the insular cortex (IC) in morphine-induced conditioned taste avoidance. The results of Experiment 1 revealed that IC lesions impaired taste neophobia, retarded acquisition of conditioned saccharin avoidance and apparently attenuated the magnitude of that response at asymptote. Using neurologically intact subjects, Experiment 2 established that a safe and familiar saccharin stimulus supports substantially weaker conditioned avoidance at asymptote than does a potentially dangerous and novel saccharin stimulus. This pattern of results does not support the hypothesis that IC lesions disrupt the learning mechanism responsible for morphine-induced conditioned taste avoidance. The data are, however, consistent with the hypothesis that IC lesions impair the perception of the danger and/or novelty of the taste stimulus.

An early study reported that, unlike sham-operated rats, rats made anosmic by olfactory bulbectomy (OBX) failed to compensate for the dilution of their diet with nonnutritive bulk by increasing their food intake. In the present study, the effects of a glucoprivic challenge, intraperitoneal-administered 350 mg/kg 2-deoxy-D-glucose (2-DG), on food intake were measured in OBX and sham-operated female rats. Sham-operated rats significantly increased their food intake, but in two separate experiments OBX rats displayed no increase in food intake during the first 2 h following administration. Blood glucose levels were nearly identical in both groups. Body weights and daily food intakes of OBX rats did not differ from the sham-operated controls throughout the studies. Bulbectomized rats also displayed a normal drinking response after an intraperitoneal injection of 1M hypertonic saline. Hypothalamic nuclei and the neural pathways mediating taste have been implicated in the feeding response to 2-DG. The present results suggest that olfactory input and olfactory neural pathways also mediate, at least in part, the feeding response to a glucoprivic challenge induced by intraperitoneal injection of 2-DG.

Intake of an unconditionally preferred taste stimulus (e.g., saccharin) is reduced by contingent administration of a drug of abuse (e.g., morphine). We examined the influence of insular cortex (IC) lesions on morphine-induced suppression of an olfactory cue and two taste stimuli with different levels of perceived innate reward value. Two major findings emerged from this study. First, morphine suppressed intake of an aqueous odor as well as each taste stimulus in neurologically intact rats. Second, IC lesions disrupted morphine-induced suppression of the taste stimuli but not the aqueous odor cue. These results indicate that the perceived innate reward value of the CS is not a factor that governs drug-induced intake suppression.

The hypothalamic control of energy balance is regulated by a complex network of neuropeptide-releasing neurons. Although the effect of these neuropeptides on individual aspects of energy homoeostasis has been studied, the coordinated response of these effects has not been comprehensively investigated. We have simultaneously monitored a number of metabolic parameters following intracerebroventricular (ICV) administration of 1 and 3 nmol of neuropeptides with established roles in the regulation of feeding, activity and metabolism. Ad libitum- fed rats received the orexigenic neuropeptides neuropeptide Y (NPY), agouti-related protein (AgRP), melanin-concentrating hormone (MCH) or orexin-A. Overnight-food-deprived rats received an ICV injection of the anorectic peptides alpha-melanocyte-stimulating hormone (MSH), corticotrophin-releasing factor (CRF) or neuromedin U (NMU).

Our results reveal the temporal sequence of the effects of these neuropeptides on both energy intake and expenditure, highlighting key differences in their function as mediators of energy balance. NPY and AgRP increased feeding and decreased oxygen consumption, with the effects of AgRP being more prolonged. In contrast, orexin-A increased both feeding and oxygen consumption, consistent with an observed increase in activity. The potent anorexigenic effects of CRF were accompanied by a prolonged increase in activity, whereas NMU injection resulted in significant but short-lasting inhibition of food intake, ambulatory activity and oxygen consumption. alpha-MSH injection resulted in significant increases in both ambulatory activity and oxygen consumption, and reduced food intake following administration of 3 nmol of the peptide.

We have for the first time, simultaneously measured several metabolic parameters following hypothalamic administration of a number of neuropeptides within the same experimental system. This work has shown the interrelated effects of these neuropeotides on activity, energy expenditure and food intake, thus facilitating comparison between the different hypothalamic systems.

Rats avoid intake of a palatable taste cue when paired with all drugs of abuse tested. Evidence suggests that, at least for morphine and cocaine, rats avoid the taste cue because they are anticipating the rewarding properties of the drug. Thus, the suppressive effects of a rewarding sucrose solution and cocaine, but not those of the putatively aversive agent, lithium chloride (LiCl), are exaggerated in drug-sensitive Lewis rats. Likewise, the suppressive effects of sucrose and morphine, but not those of LiCl, are eliminated by bilateral lesions of the gustatory thalamus. Unlike morphine and cocaine, it is less clear whether rewarding or aversive drug properties are responsible for ethanol-induced suppression of intake of a taste cue. The present set of studies tests whether, like cocaine, ethanol-induced suppression of intake of a taste cue also is greater in the drug-sensitive Lewis rats and whether the suppressive effects of the drug are prevented by bilateral lesions of the taste thalamus.

In Experiment 1, fluid-deprived Lewis and Fischer rats were given 5-minute access to 0.15% saccharin and then injected with saline or a range of doses of ethanol (0.5, 0.75, 1.0, or 1.5 g/kg). There was a total of 6 such pairings. In Experiments 2 and 3, Sprague-Dawley rats received bilateral electrophysiologically guided lesions of the gustatory thalamus. After recovery, suppression of intake of the saccharin cue was evaluated following repeated daily pairings with either a high (1.5 g/kg) or a low (0.75 g/kg) dose of ethanol.

Ethanol-induced suppression of intake of the saccharin conditioned stimulus (CS) did not differ between the drug-sensitive Lewis rats relative to the less-sensitive Fischer rats. Lesions of the taste thalamus, however, prevented the suppressive effect of the 0.75 g/kg dose of the drug, but had no impact on the suppressive effect of the 1.5 g/kg dose of ethanol.

The results suggest that the suppressive effects of ethanol on CS intake are mediated by both rewarding and aversive consequences, varying as a function of dose.

In the words of the late Charles Flaherty, reward comparison is commonplace. Rats and man, it appears, compare all rewards and this capacity likely contributes to our ability to select the most appropriate reward/behavior (food, water, salt, sex), at the most ideal level (e.g., a certain sweetness), at any given time. A second advantage of our predisposition for reward comparison is that the availability of rich alternative rewards can protect against our becoming addicted to any single reward/behavior. Thus, the potential protective effects of natural rewards/enrichment are addressed. Despite this, behavior can become inflexible when, through the development of addiction, stress, drug, or cues elicit craving, withdrawal, and ultimately, drug-seeking. Drug-seeking corresponds with a 'window of inopportunity', when even potent natural rewards have little or no impact on behavior. During this time, there is a unitary solution to the need state, and that solution is drug. The present animal model explores this 'window of inopportunity' when natural rewards are devalued and drug-seeking is engaged and considers a mode of possible intervention.

Rats avoid intake of a gustatory cue following pairings with a drug of abuse, such as morphine or cocaine. Despite the well-established rewarding properties of these drugs, the reduction in intake of the taste cue has been interpreted as a conditioned taste aversion for decades. In 1997, I proposed the reward comparison hypothesis suggesting that rats avoided intake of the drug-associated taste cue because the value of the taste cue pales in comparison to the highly rewarding drug of abuse expected in the near future. In this issue of Behavioral Neuroscience, A. C. W. Huang and S. Hsiao challenge the reward comparison hypothesis by showing parallels between amphetamine and LiCl-induced suppression of CS intake. This commentary addresses the current state of the reward comparison hypothesis in the context of the experiments completed by Huang and Hsiao and their new task-dependent drug effects hypothesis.

Lesions of the amygdala have long been known to produce hyperphagia and obesity in cats, dogs, and monkeys, but only recently have studies with rats determined that the effective site is the posterodorsal amygdala (PDA)-the posterodorsal medial amygdaloid nucleus and the intra-amygdaloid bed nucleus of the stria terminalis. There is a sex difference; female rats with PDA lesions display greater weight gain than male rats. In the brains of female rats with obesity-inducing PDA lesions, there is a dense pattern of axonal degeneration in the capsule of the ventromedial hypothalamus (VMH) and other targets of the stria terminalis. Transections of the dorsal component of the stria terminalis also result in hyperphagia and obesity in female rats. Similar to rats with VMH lesions, rats with PDA lesions are hyperinsulinemic during food restriction and greatly prefer high-carbohydrate diets. The PDA is also a critical site for some aspects of rodent sexual behavior, particularly those that depend on olfaction, and the pattern of degeneration observed after obesity-inducing PDA lesions is remarkably parallel to the circuit that has been proposed to mediate sexual behavior. Medial amygdaloid lesions disrupt the normal feeding pattern and result in impaired responses to caloric challenges, and there is evidence that these behavioral changes are also due to a disruption of olfactory input. With its input from the olfactory bulbs and connections to the VMH, the PDA may be a nodal point at which olfactory and neuroendocrine stimuli are integrated to affect feeding behavior.

Rats suppress intake of a saccharin cue when paired with a drug of abuse such as morphine or cocaine. Relative to Lewis rats, Fischer rats exhibit greater avoidance of a saccharin cue following saccharin-morphine pairings. The present study used the mu agonist, [D-Ala2,N-MePhe4,Gly-ol5]enkephalin (DAMGO), to test whether strain differences in sensitivity of the mu receptor contribute to this effect. Water-deprived Lewis and Fischer rats were given 5 min access to 0.15% saccharin followed by an icv injection of either DAMGO (0.5 microg/1 microl/rat) or an equal volume of saline. There were six taste-drug pairings occurring at 48 h intervals. The results showed that, relative to the saline treated controls, all rats reduced intake of the saccharin cue following saccharin-DAMGO pairings. No differences occurred between strains. These data suggest that greater morphine-induced suppression of saccharin intake by the Fischer rats is not likely mediated by differences in sensitivity of the mu receptor. Other mechanisms are implicated.

Drugs of abuse such as cocaine induce a paradoxical aversive effect when paired with a novel taste. When a novel gustatory cue is paired with drugs of abuse the resulting conditioned effect is the avoidance of the novel taste. A conditioning paradigm was developed in order to pair saccharin with self-administered cocaine. Rats were trained to lever-press for sweetened milk in an operant chamber and then implanted with an intrajugular catheter for cocaine self-administration (SA). After recovery from surgery, food and water access were restricted and the operant behavior was reestablished using contingent milk. Pairings of 10-min saccharin access followed by 1-h cocaine (0.125 mg/kg per injection) SA sessions were alternated daily with pairings of 10-min water access followed by 30-min SA sessions of oral milk and i.v. saline, delivered simultaneously. Pairings were conducted once a day for 10 days. After four sessions of cocaine self-administration there was no significant decrease in saccharin intake. However, rats that avoided saccharin also self-administered more cocaine than non-avoiding rats. These results suggest that the development of taste aversion is accompanied by an acceptance of the drug rather than an aversion to it.

Rats suppress intake of a saccharin conditioned stimulus (CS) when paired with all drugs of abuse tested including morphine, cocaine, heroin, amphetamine, and ethanol. Although most of these drugs suppress intake when administered via a range of routes, the efficacy of cocaine is an exception. Specifically, cocaine-induced suppression of saccharin intake is much greater when administered subcutaneously than when administered intraperitoneally. The subcutaneous route of administration of cocaine, however, is somewhat problematic because, unless diluted, can cause stark necrosis. The present study, then, reexamined the effectiveness of intraperitoneal cocaine using less restrictive deprivation regimens that are known to facilitate the expression of the phenomenon. The results showed that, while only a 10- and 20-mg/kg dose of cocaine suppressed intake of the saccharin CS when evaluated in moderately water-deprived rats, all doses tested (i.e., 5, 10, and 20 mg/kg) significantly reduced CS intake when saccharin-cocaine pairings were evaluated in rats maintained on food and water ad libitum. Taken together, these data show that rats will readily avoid intake of a saccharin cue when paired with the intraperitoneal administration of cocaine and that the magnitude of the effect is augmented when examined in a need-free state.

The volume of fluid that rats acquire with each lick was systematically varied across short-term tests with 12.5% glucose (Experiment 1) or 12.5% maltodextrin (Experiment 2). For glucose, rats increased the number of licks emitted as lick volume was reduced such that meal size remained remarkably stable across all (8, 4, and 2 microl) but the smallest (1 microl) lick volume conditions tested. Rats similarly compensated for lick volume reduction (8 to 4 microl) with maltodextrin by approximately doubling the number of licks emitted. Meal duration and a number of lick-microstructural parameters (initial ingestion rate, mean burst duration, terminal lick and ingestion rates, and burst duration) were not correlated with the intake outcome insofar as they varied significantly across conditions over which intake remained stable. Thus, in response to lick volume manipulation, rats demonstrated an impressive degree of behavioral flexibility in what may be regarded as a defense of meal size.